Anemia of chronic kidney disease: Treat it, but not too aggressively

Article Type
Changed
Wed, 08/16/2017 - 15:17
Display Headline
Anemia of chronic kidney disease: Treat it, but not too aggressively

Anemia is a frequent complication of chronic kidney disease, occurring in over 90% of patients receiving renal replacement therapy. It is associated with significant morbidity and mortality. While its pathogenesis is typically multifactorial, the predominant cause is failure of the kidneys to produce enough endogenous erythropoietin. The clinical approval of recombinant human erythropoietin in 1989 dramatically changed the treatment of anemia of chronic kidney disease, but randomized controlled trials yielded disappointing results when erythropoiesis-stimulating agents (ESAs) were used to raise hemoglobin to normal levels.

This article reviews the epidemiology and pathophysiology of anemia of chronic kidney disease and discusses the complicated and conflicting evidence regarding its treatment.

DEFINITION AND PREVALENCE

Anemia is defined as a hemoglobin concentration less than 13.0 g/dL for men and less than 12.0 g/dL for premenopausal women.1 It is more common in patients with impaired kidney function, especially when the glomerular filtration rate (GFR) falls below 60 mL/min. It is rare at GFRs higher than 80 mL/min,2 but as the GFR falls, the severity of the anemia worsens3 and its prevalence increases: almost 90% of patients with a GFR less than 30 mL/min are anemic.4

RENAL ANEMIA IS ASSOCIATED WITH BAD OUTCOMES

Anemia in chronic kidney disease is independently associated with risk of death. It is also an all-cause mortality multiplier, ie, it magnifies the risk of death from other disease states.5

In observational studies, anemia was associated with faster progression of left ventricular hypertrophy, inflammation, and increased myocardial and peripheral oxygen demand, thereby leading to worse cardiac outcomes with increased risk of myocardial infarction, coronary revascularization, and readmission for heart failure.6–8 Anemia is also associated with fatigue, depression, reduced exercise tolerance, stroke, and increased risk of rehospitalization.9–13

RENAL ANEMIA IS MULTIFACTORIAL

Anemia of chronic kidney disease is typically attributed to the decrease of erythropoietin production that accompanies the fall in GFR. However, the process is multifactorial, with several other contributing factors: absolute and functional iron deficiency, folate and vitamin B12 deficiencies, reduced red blood cell life span, and suppression of erythropoiesis by the uremic milieu.14

While it was once thought that chronic kidney disease leads to loss of erythropoietin-producing cells, it is now known that downregulation of hypoxia-inducible factor (HIF; a transcription factor) is at least partially responsible for the decrease in erythropoietin production15,16 and that this downregulation is reversible (see below).

ERYTHROPOIETIN, IRON, AND RED BLOOD CELLS

Erythropoietin production is triggered by hypoxia, mediated by HIF

Erythropoietin is produced primarily in the deep cortex and outer medulla of the kidneys by a special population of peritubular interstitial cells.17 The parenchymal cells of the liver also produce erythropoietin, but much less.18

Figure 1.

The rate of renal erythropoietin synthesis is determined by tissue oxygenation rather than by renal blood flow; production increases as the hemoglobin concentration drops and the arterial oxygen tension decreases (Figure 1).19

The gene for erythropoietin is located on chromosome 7 and is regulated by HIF. HIF molecules are composed of an alpha subunit, which is unstable at high Po2, and a beta subunit, constitutively present in the nucleus.20

In hypoxic conditions, the HIF dimer is transcriptionally active and binds to specific DNA recognition sequences called hypoxia-response elements. Gene transcription is upregulated, leading to increased production of erythropoietin.21

Under normal oxygen tension, on the other hand, the proline residue of the HIF alpha subunit is hydroxylated. The hydroxylated HIF alpha subunit is then degraded by proteasomal ubiquitylation, which is mediated by the von Hippel-Lindau tumor-suppressor gene pVHL.22 Degradation of HIF alpha prevents formation of the HIF heterodimers. HIF therefore cannot bind to the hypoxia-response elements, and erythropoietin gene transcription does not occur.23

Thus, in states of hypoxia, erythropoietin production is upregulated, whereas with normal oxygen tension, production is downregulated.

Erythropoietin is essential for terminal maturation of erythrocytes

Erythropoietin is essential for terminal maturation of erythrocytes.24 It is thought to stimulate the growth of erythrogenic progenitors: burst-forming units-erythroid (BFU-E) and colony-forming units-erythroid (CFU-E). In the absence of erythropoietin, BFU-E and CFU-E fail to differentiate into mature erythrocytes.25

Binding of erythropoietin to its receptor sets off a series of downstream signals, the most important being the signal transducer and activator of transcription 5 (STAT5). In animal studies, STAT5 was found to inhibit apoptosis through the early induction of an antiapoptotic gene, Bcl-xL.26

Iron metabolism is controlled by several proteins

Iron is characterized by its capacity to accept or donate electrons. This unique property makes it a crucial element in many biochemical reactions such as enzymatic activity, DNA synthesis, oxygen transport, and cell respiration.

Figure 2. Iron absorption and metabolism is controlled by several proteins. DMT1 = divalent metal transporter 1; FPN = ferroportin; Hgb = hemoglobin; TF = transferrin, TFR = transferrin receptor

Iron metabolism is under the control of several proteins that play different roles in its absorption, recycling, and loss (Figure 2).27

Dietary iron exists primarily in its poorly soluble trivalent ferric form (Fe3+), and it needs to be reduced to its soluble divalent ferrous form (Fe2+) by ferric reductase to be absorbed. Ferrous iron is taken up at the apical side of enterocytes by a divalent metal transporter (DMT1) and is transported across the brush border.28

To enter the circulation, iron has to be transported across the basolateral membrane by a transporter called ferroportin.29 Ferroportin is also found in placental syncitiotrophoblasts, where it transfers iron from mother to fetus, and in macrophages, where it allows recycling of iron scavenged from damaged cells back into the circulation.30 Upon its release, the ferrous iron is oxidized to the ferric form and loaded onto transferrin. This oxidation process involves hephaestin, a homologue of the ferroxidase ceruloplasmin.31

In the plasma, iron is bound to transferrin, and under normal circumstances one-third of transferrin is saturated with iron.32 Transferrin receptors are present on most cells but are most dense on erythroid precursors. Each transferrin receptor can bind two transferrin molecules. After binding to transferrin, the transferrin receptor is endocytosed, and the iron is released into acidified vacuoles. The transferrin-receptor complex is then recycled to the surface.33

Ferritin is the cellular storage protein for iron, and it can store up to 4,500 atoms of iron within its spherical cavity.34 The serum level of ferritin reflects overall storage, with 1 ng/mL of ferritin indicating 10 mg of total iron stores.35 Ferritin is also an acute-phase reactant, and plasma levels can increase in inflammatory states such as infection or malignancy. As such, elevated ferritin does not necessarily indicate elevated iron stores.

Iron is lost in sweat, shed skin cells, and sloughed intestinal mucosal cells. However, there is no specific mechanism of iron excretion from the human body. Thus, iron is mainly regulated at the level of intestinal absorption. The iron exporter ferroportin is upregulated by the amount of available iron and is degraded by hepcidin.36

Hepcidin is a small cysteine-rich cationic peptide that is primarily produced in the liver, with some minor production also occurring in the kidneys.37 Transcription of the gene encoding hepcidin is downregulated by anemia and hypoxia and upregulated by inflammation and elevated iron levels.38 Transcription of hepcidin leads to degradation of ferroportin and a decrease in intestinal iron absorption. On the other hand, anemia and hypoxia inhibit hepcidin transcription, which allows ferroportin to facilitate intestinal iron absorption.

TREATMENT OF RENAL ANEMIA

Early enthusiasm for erythropoietin agents

Androgens started to be used to treat anemia of end-stage renal disease in 1970,39,40 and before the advent of recombinant human erythropoietin, they were a mainstay of nontransfusional therapy for anemic patients on dialysis.

The approval of recombinant human erythropoietin in 1989 drastically shifted the treatment of renal anemia. While the initial goal of treating anemia of chronic kidney disease with erythropoietin was to prevent blood transfusions,41 subsequent studies showed that the benefits might be far greater. Indeed, an initial observational trial showed that erythropoiesis-stimulating agents (ESAs) were associated with improved quality of life,42 improved neurocognitive function,43,44 and even cost savings.45 The benefits also extended to major outcomes such as regression of left ventricular hypertrophy,46 improvement in New York Heart Association class and cardiac function,47 fewer hospitalizations,48 and even reduction of cardiovascular mortality rates.49

As a result, ESA use gained popularity, and by 2006 an estimated 90% of dialysis patients were receiving these agents.50 The target and achieved hemoglobin levels also increased, with mean hemoglobin levels in hemodialysis patients being raised from 9.7 to 12 g/dL.51

Disappointing results in clinical trials of ESAs to normalize hemoglobin

To prospectively study the effects of normalized hemoglobin targets, four randomized controlled trials were conducted (Table 1):

  • The Normal Hematocrit Study (NHCT)52
  • The Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial53
  • The Cardiovascular Risk Reduction by Early Anemia Treatment (CREATE) trial54
  • The Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT).55

These trials randomized patients to either higher “normal-range” hemoglobin targets or to lower target hemoglobin levels.

Their findings were disappointing and raised several red flags about excessive use of ESAs. The trials found no benefit in higher hemoglobin targets, and in fact, some of them demonstrated harm in patients randomized to higher targets. Notably, higher hemoglobin targets were associated with significant side effects such as access-site  thrombosis,52 strokes,55 and possibly cardiovascular events.54,55 Only the CREATE trial was able to demonstrate a quality-of-life benefit for the high-target group.54 

It remains unclear whether these adverse events were from the therapy itself or from an increased morbidity burden in the treated patients. Erythropoietin use is associated with hypertension,56 thought to be related to endothelin-mediated vasoconstriction.57 In our experience, this is most evident when hemoglobin levels are normalized with ESA therapy. Cycling of erythropoietin levels between extreme levels can lead to vascular remodeling, which may also be related to its cardiovascular effects.57

A noticeable finding in several of these trials was that patients failed to achieve the higher hemoglobin target despite the use of very high doses of ESA. Reanalysis of data from the CHOIR and CREATE trials showed that the patients who had worse outcomes were more likely to have required very high doses without achieving their target hemoglobin.58,59 Indeed, patients who achieved the higher target hemoglobin levels, usually at lower ESA doses, had better outcomes. This suggested that the need for a higher dose was associated with poorer outcomes, either as a marker of comorbidity or due to yet undocumented side effects of such high doses.

General approach to therapy

Before attributing anemia to chronic kidney disease, a thorough evaluation should be conducted to look for any reversible process that could be contributing to the anemia.

The causes of anemia are numerous and beyond the scope of this review. However, among the common causes of anemia in chronic kidney disease are deficiencies of iron, vitamin B12, and folate. Therefore, guidelines recommend checking iron, vitamin B12, and folate levels in the initial evaluation of anemia.60

Iron deficiency in particular is very common in chronic kidney disease patients and is present in nearly all dialysis patients.61 Hemodialysis patients are estimated to lose 1 to 3 g of iron per year as a result of blood loss in the dialysis circuit and increased iron utilization secondary to ESA therapy.62

However, in contrast to the general population, in which the upper limits of normal for iron indices are well defined, high serum ferritin levels appear to be poorly predictive of hemoglobin responsiveness in dialysis patients.63,64 Thus, the cutoffs that define iron responsiveness are much higher than standard definitions for iron deficiency.65,66 The Dialysis Patients’ Response to IV Iron With Elevated Ferritin (DRIVE) study showed that dialysis patients benefit from intravenous iron therapy even if their ferritin is as high as 1,200 ng/mL, provided their transferrin saturation is below 30%.67

Of note, erythropoietin levels cannot be used to distinguish renal anemia from other causes of anemia. Indeed, patients with renal failure may have “relative erythropoietin deficiency,” ie, “normal” erythropoietin levels that are actually too low in view of the degree of anemia.68,69 In addition to the decreased production capacity by the kidney, there appears to be a component of resistance to the action of erythropoietin in the bone marrow.

For these reasons, there is no erythropoietin level that can be considered “inadequate” or defining of renal anemia. Thus, measuring erythropoietin levels is not routinely recommended in the evaluation of renal anemia.

 

 

Two ESA preparations

The two ESAs that have traditionally been used in the treatment of renal anemia are recombinant human erythropoietin and darbepoietin alfa. They appear to be equivalent in terms of safety and efficacy.70 However, darbepoietin alfa has more sialic acid molecules, giving it a higher potency and longer half-life and allowing for less-frequent injections.71,72

In nondialysis patients, recombinant human erythropoietin is typically given every 1 to 2 weeks, whereas darbepoietin alfa can be given every 2 to 4 weeks. In dialysis patients, recombinant human erythropoietin is typically given 3 times per week with every dialysis treatment, while darbepoietin alfa is given once a week.

Target hemoglobin levels: ≤ 11.5 g/dL

In light of the four trials described in Table 1, the international Kidney Disease: Improving Global Outcomes (KDIGO) guidelines60 recommend the following (Table 2):

For patients with chronic kidney disease who are not on dialysis, ESA therapy should not be initiated if the hemoglobin level is higher than 10 g/dL. If the hemoglobin level is lower than 10 g/dL, ESA therapy can be initiated, but the decision needs to be individualized based on the rate of fall of hemoglobin concentration, prior response to iron therapy, the risk of needing a transfusion, the risks related to ESA therapy, and the presence of symptoms attributable to anemia.

For patients on dialysis, ESA therapy should be used when the hemoglobin level is between 9 and 10 g/dL to avoid having the hemoglobin fall below 9 g/dL.

In all adult patients, ESAs should not be used to intentionally increase the hemoglobin level above 13 g/dL but rather to maintain levels no higher than 11.5 g/dL. This target is based on the observation that adverse outcomes were associated with ESA use with hemoglobin targets higher than 13 g/dL (Table 1).

Target iron levels

Regarding iron stores, the guidelines recommend the following:

For adult patients with chronic kidney disease who are not on dialysis, iron should be given to keep transferrin saturation above 20% and ferritin above 100 ng/mL. Transferrin saturation should not exceed 30%, and ferritin levels should not exceed 500 ng/mL.

For adult patients on dialysis, iron should be given to maintain transferrin saturation above 30% and ferritin above 200 ng/mL.

The upper limits of ferritin and transferrin saturation are somewhat controversial, as the safety of intentionally maintaining respective levels greater than 30% and 500 ng/mL has been studied in very few patients. Transferrin saturation should in general not exceed 50%.

High ferritin levels are associated with higher death rates, but whether elevation of ferritin levels is a marker of excessive iron administration rather than a nonspecific acute-phase reactant is not clear. The 2006 guidelines60 cited upper ferritin limits of 500 to 800 ng/mL. However, the more recent DRIVE trial67 showed that patients with ferritin levels of 500 to 1,200 ng/mL will respond to intravenous administration of iron with an increase in their hemoglobin levels. This has led many clinicians to adopt a higher ferritin limit of 1,200 ng/mL.

Hemosiderosis, or excess iron deposition, was a known consequence of frequent transfusions in patients with end-stage renal disease before ESA therapy was available. However, there have been no documented cases of clinical iron overload from iron therapy using current guidelines.73

These algorithms are nuanced, and the benefit of giving intravenous iron should always be weighed against the risks of short-term acute toxicity and infection. Treatment of renal anemia not only requires in-depth knowledge of the topic, but also familiarity with the patient’s specific situation. As such, it is not recommended that clinicians unfamiliar with the treatment of renal anemia manage its treatment.

PARTICULAR CIRCUMSTANCES

Inflammation and ESA resistance

While ESAs are effective in treating anemia in many cases, in many patients the anemia fails to respond. This is of particular importance, since ESA hyporesponsiveness has been found to be a powerful predictor of cardiovascular events and death.74 It is unclear, however, whether high doses of ESA are inherently toxic or whether hyporesponsiveness is a marker of adverse outcomes related to comorbidities.

KDIGO defines initial hyporesponsiveness as having no increase in hemoglobin concentration after the first month of appropriate weight-based dosing, and acquired hyporesponsiveness as requiring two increases in ESA doses up to 50% beyond the dose at which the patient had originally been stable.60 Identifying ESA hyporesponsiveness should lead to an intensive search for potentially correctable factors.

The two major factors accounting for the state of hyporesponsiveness are inflammation and iron deficiency.75,76

Inflammation. High C-reactive protein levels have been shown to predict resistance to erythropoietin in dialysis patients.77 The release of cytokines such as tumor necrosis factor alpha, interleukin 1, and interferon gamma has an inhibitory effect on erythropoiesis.78 Additionally, inflammation can alter the response to ESAs by disrupting the metabolism of iron79 through the release of hepcidin, as previously discussed.38 These reasons likely account for the observed lower response to ESAs in the setting of acute illness and explain why ESAs are not recommended for correcting acute anemia.80

Iron deficiency also can blunt the response to ESAs. Large amounts of iron are needed for effective erythropoietic bursts. As such, iron supplementation is now a recognized treatment of renal anemia.81

Other factors associated with hyporesponsiveness include chronic occult blood loss, aluminum toxicity, cobalamin or folate deficiencies, testosterone deficiency, inadequate dialysis, hyperparathyroidism, and superimposed primary bone marrow disease,82,83 and these should be addressed in patients whose anemia does not respond as expected to ESA therapy. A summary of the main causes of ESA hyporesponsiveness, their reversibility, and recommended treatments is presented in Table 3.

Antibody-mediated pure red-cell aplasia. Rarely, patients receiving ESA therapy develop antibodies that neutralize both the ESA and endogenous erythropoietin. The resulting syndrome, called antibody-mediated pure red-cell aplasia, is characterized by the sudden development of severe transfusion-dependent anemia. This has historically been connected to epoetin beta, a formulation not in use in the United States. However, cases have been documented with epoetin alfa and darbepoetin. The incidence rate is low with subcutaneous ESA use, estimated at 0.5 cases per 10,000 patient-years84 and anecdotal with intravenous ESA.85 The definitive diagnosis requires demonstration of neutralizing antibodies against erythropoietin. Parvovirus infection should be excluded as an alternative cause of pure red­cell aplasia.

ANEMIA IN CANCER PATIENTS

ESAs are effective in raising hemoglobin levels and reducing transfusion requirements in patients with chemotherapy-induced anemia.86 However, there are data linking the use of ESAs to shortened survival in patients who have a variety of solid tumors.87

Several mechanisms have been proposed to explain this rapid disease progression, most notably acceleration in tumor growth88–90 by stimulation of erythropoietin receptors on the surface of the tumor cells, leading to increased tumor angiogenesis.91,92

For these reasons, treatment of renal anemia in the setting of active malignancy should be referred to an oncologist.

NOVEL TREATMENTS

Several new agents for treating renal anemia are currently under review.

Continuous erythropoiesis receptor activator

Continuous erythropoiesis receptor activator is a pegylated form of recombinant human erythropoietin that has the ability to repeatedly activate the erythropoietin receptor. It appears to be similar to the other forms of erythropoietin in terms of safety and efficacy in both end-stage renal disease93 and chronic kidney disease.94 It has the advantage of an extended serum half-life, which allows for longer dosing intervals, ie, every 2 weeks. Its use is currently gaining popularity in the dialysis community.

HIF stabilizers

Our growing understanding of the physiology of erythropoietin offers new potential treatment targets. As previously described, production of erythropoietin is stimulated by HIFs. In order to be degraded, these HIFs are hydroxylated at their proline residues by a prolyl hydroxylase. A new category of drugs called prolyl-hydroxylase inhibitors (PDIs) offers the advantage of stabilizing the HIFs, leading to an increase in erythropoietin production.

In phase 1 and 2 clinical trials, these agents have been shown to increase hemoglobin in both end-stage renal disease and chronic kidney disease patients15,16 but not in anephric patients, demonstrating a renal source of the erythropoietin production even in nonfunctioning kidneys. The study of one PDI agent (FG 2216) was halted temporarily after a report of death from fulminant hepatitis, but the other (FG 4592) continues to be studied in a phase 2 clinical trial.95,96

TAKE-HOME POINTS

  • Anemia of renal disease is a common condition that is mainly caused by a decrease in erythropoietin production by the kidneys.
  • While anemia of renal disease can be corrected with ESAs, it is necessary to investigate and rule out underlying treatable conditions such as iron or vitamin deficiencies before giving an ESA.
  • Anemia of renal disease is associated with significant morbidity such as increased risk of left ventricular hypertrophy, myocardial infarction, and heart failure, and has been described as an all-cause mortality multiplier.
  • Unfortunately, the only undisputed benefit of treatment to date remains the avoidance of blood transfusions. Furthermore, the large randomized controlled trials that looked at the benefits of ESA have shown that their use can be associated with increased risk of cardiovascular events. Therefore, use of an ESA in end-stage renal disease should never target a normal hemoglobin levels but rather aim for a hemoglobin level of no more than 11.5 g/dL.
  • Use of an ESA in chronic kidney disease should be individualized and is not recommended to be started unless the hemoglobin level is less than 10 g/dL.
  • Several newer agents for renal anemia are currently under review. A pegylated form of recombinant human erythropoietin has an extended half-life, and a new and promising category of drugs called HIF stabilizers is currently under study.
References
  1. World Health Organization (WHO). Nutritional anaemias: report of a WHO scientific group. Geneva, Switzerland: World Health Organization, 1968.
  2. Hsu CY, McCulloch CE, Curhan GC, et al. Epidemiology of anemia associated with chronic renal insufficiency among adults in the United States: results from the Third National Health and Nutrition Examination Survey. J Am Soc Nephrol 2002; 13:504–510.
  3. Radtke HW, Claussner A, Erbes PM, Scheuermann EH, Schoeppe W, Koch KM. Serum erythropoetin concentration in chronic renal failure: relationship to degree of anemia and excretory renal function. Blood 1979; 54:877–884.
  4. Kazmi WH, Kausz AT, Khan S, et al. Anemia: an early complication of chronic renal insufficiency. Am J Kidney Dis 2001; 38:803–812.
  5. United States Renal Data System. Chapter 3. Morbidity & mortality in patients with CKD. www.usrds.org/2012/view/v1_03.aspx. Accessed June 9, 2016.
  6. Horwich TB, Fonarow GC, Hamilton MA, MacLellan WR, Borenstein J. Anemia is associated with worse symptoms, greater impairment in functional capacity and a significant increase in mortality in patients with advanced heart failure. J Am Coll Cardiol 2002; 39:1780–1786.
  7. Mark DB, Felker GM. B-type natriuretic peptide: a biomarker for all seasons? N Engl J Med 2004; 350:718–720.
  8. Walker AM, Schneider G, Yeaw J, Nordstrom B, Robbins S, Pettitt D. Anemia as a predictor of cardiovascular events in patients with elevated serum creatinine. J Am Soc Nephrol 2006; 17:2293–2298.
  9. Abramson JL, Jurkovitz CT, Vaccarino V, Weintraub WS, McClellan W. Chronic kidney disease, anemia, and incident stroke in a middle-aged, community-based population: the ARIC Study. Kidney Int 2003; 64:610–615.
  10. Sarnak MJ, Tighiouart H, Manjunath G, et al. Anemia as a risk factor for cardiovascular disease in the Atherosclerosis Risk in Communities (ARIC) study. J Am Coll Cardiol 2002; 40:27–33.
  11. McClellan WM, Flanders WD, Langston RD, Jurkovitz C, Presley R. Anemia and renal insufficiency are independent risk factors for death among patients with congestive heart failure admitted to community hospitals: a population-based study. J Am Soc Nephrol 2002; 13:1928–1936.
  12. Xia H, Ebben J, Ma JZ, Collins AJ. Hematocrit levels and hospitalization risks in hemodialysis patients. J Am Soc Nephrol 1999; 10:1309–1316.
  13. Collins AJ, Li S, St Peter W, et al. Death, hospitalization, and economic associations among incident hemodialysis patients with hematocrit values of 36 to 39%. J Am Soc Nephrol 2001; 12:2465–2473.
  14. Agarwal AK. Practical approach to the diagnosis and treatment of anemia associated with CKD in elderly. J Am Med Dir Assoc 2006; 7(suppl 9):S7–S12.
  15. Bernhardt WM, Wiesener MS, Scigalla P, et al. Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD. J Am Soc Nephrol 2010; 21:2151–2156.
  16. Provenzano R, Fadda G, Bernardo M, et al. FG-2216, a novel oral HIF-PHI, stimulates erythropoiesis and increases hemoglobin concentration in patients with non-dialysis CKD. Am J Kidney Dis 2008; 51:B80.
  17. Maxwell PH, Osmond MK, Pugh CW, et al. Identification of the renal erythropoietin-producing cells using transgenic mice. Kidney Int 1993; 44:1149–1162.
  18. Maxwell PH, Ferguson DJ, Nicholls LG, et al. Sites of erythropoietin production. Kidney Int 1997; 51:393–401.
  19. Jelkmann W. Erythropoeitin: structure, control of production and function. Physiol Rev 1992; 72:449–489.
  20. Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 1995; 92:5510–5514.
  21. Wang GL, Semenza GL. Purification and characterization of hypoxia-inducible factor 1. J Biol Chem 1995; 270:1230–1237.
  22. Maxwell PH, Wiesener MS, Chang GW, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 1999; 399:271–275.
  23. Salceda S, Caro J. Hypoxia-inducible factor 1alpha protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. J Biol Chem 1997; 272:22642–22647.
  24. Malik J, Kim AR, Tyre KA, Cherukuri AR, Palis J. Erythropoietin critically regulates the terminal maturation of murine and human primitive erythroblasts. Haematologica 2013; 98:1778–1787.
  25. Wu H, Liu X, Jaenisch R, Lodish HF. Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor. Cell 1995; 83:59–67.
  26. Socolovsky M, Nam H, Fleming MD, Haase VH, Brugnara C, Lodish HF. Ineffective erythropoiesis in Stat5a(-/-)5b(-/-) mice due to decreased survival of early erythroblasts. Blood 2001; 98:3261–3273.
  27. Papanikolaou G, Pantopoulos K. Iron metabolism and toxicity. Toxicol Appl Pharmacol 2005; 202:199–211.
  28. Conrad ME, Umbreit JN. Pathways of iron absorption. Blood Cells Mol Dis 2002; 29:336–355.
  29. Frazer DM, Anderson GJ. The orchestration of body iron intake: how and where do enterocytes receive their cues? Blood Cells Moll Dis 2003; 30:288–297.
  30. Donovan A, Lima CA, Pinkus JL, et al. The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab 2005; 1:191–200.
  31. Vulpe CD, Kuo YM, Murphy TL, et al. Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Nat Genet 1999; 21:195–199.
  32. Bothwell TH. Overview and mechanisms of iron regulation. Nutr Rev 1995: 53:237–245.
  33. Kawabata H, Nakamaki T, Ikonomi P, Smith RD, Germain RS, Koeffler HP. Expression of transferrin receptor 2 in normal and neoplastic hematopoietic cells. Blood 2001; 98:2714–2719.
  34. Arosio P, Levi S. Cytosolic and mitochondrial ferritins in the regulation of cellular iron homeostasis and oxidative damage. Biochim Biophys Acta 2010; 1800:783–792.
  35. Finch CA, Bellotti V, Stray S, et al. Plasma ferritin determination as a diagnostic tool. West J Med 1986; 145:657–663.
  36. Delaby C, Pilard N, Goncalves AS, Beaumont C, Canonne-Hergaux F. Presence of the iron exporter ferroportin at the plasma membrane of macrophages is enhanced by iron loading and down-regulated by hepcidin. Blood 2005; 106:3979–3984.
  37. Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood 2003; 102:783–788.
  38. Nicolas G, Chauvet C, Viatte L, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest 2002; 110:1037–1044.
  39. DeGowin RL, Lavender AR, Forland M, Charleston D, Gottschalk A. Erythropoiesis and erythropoietin in patients with chronic renal failure treated with hemodialysis and testosterone. Ann Intern Med 1970; 72:913–918.
  40. Richardson JR Jr, Weinstein MB. Erythropoietic response of dialyzed patients to testosterone administration. Ann Intern Med 1970; 73:403–407
  41. Eschbach JW, Abdulhadi MH, Browne JK, et al. Recombinant human erythropoietin in anemic patients with end-stage renal disease. Results of a phase III multicenter clinical trial. Ann Intern Med 1989; 111:992–1000.
  42. Moreno F, Aracil FJ, Pérez R, Valderrábano F. Controlled study on the improvement of quality of life in elderly hemodialysis patients after correcting end-stage renal disease-related anemia with erythropoietin. Am J Kidney Dis 1996; 27:548–556.
  43. Nissenson AR, Nimer SD, Wolcott DL. Recombinant human erythropoietin and renal anemia: molecular biology, clinical efficacy, and nervous system effects. Ann Intern Med 1991; 114:402–416.
  44. Stivelman JC. Benefits of anaemia treatment on cognitive function. Nephrol Dial Transplant 2000; 15(suppl 3):29–35.
  45. Maddux FW, Shetty S, del Aguila MA, Nelson MA, Murray BM. Effect of erythropoiesis-stimulating agents on healthcare utilization, costs, and outcomes in chronic kidney disease. Ann Pharmacother 2007; 41:1761–1769.
  46. Macdougall IC, Lewis NP, Saunders MJ, et al. Long-term cardiorespiratory effects of amelioration of renal anaemia by erythropoietin. Lancet 1990; 335:489–493.
  47. Silverberg DS, Wexler D, Blum M, et al. Effects of treatment with epoetin beta on outcomes in patients with anaemia and chronic heart failure. Kidney Blood Press Res 2005; 28:41–47.
  48. Perkins R, Olson S, Hansen J, Lee J, Stiles K, Lebrun C. Impact of an anemia clinic on emergency room visits and hospitalizations in patients with anemia of CKD pre-dialysis. Nephrol Nurs J 2007; 34:167–173, 182.
  49. Locatelli F, Conte F, Marcelli D. The impact of haematocrit levels and erythropoietin treatment on overall and cardiovascular mortality and morbidity—the experience of the Lombardy Dialysis Registry. Nephrol Dial Transplant 1998; 13:1642–1644.
  50. Centers for Medicare and Medicaid Services; Kinney R. 2005 Annual Report: ESRD Clinical Performance Measures Project. Am J Kidney Dis 2006; 48(suppl 2):S1–S106.
  51. US Renal Data System. Annual Data Report 2006. www.usrds.org/adr.aspx. Accessed July 3, 2016.
  52. Besarab A, Bolton WK, Browne JK, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 1998; 339:584–590.
  53. Singh AK, Szczech L, Tang KL, et al; CHOIR Investigators. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006; 355:2085–2098.
  54. Drüeke TB, Locatelli F, Clyne N, et al; CREATE Investigators. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006; 355:2071–2084.
  55. Pfeffer MA, Burdmann EA, Chen CY, et al; TREAT Investigators. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 2009; 361:2019–2032.
  56. Kirkpantur A, Kahraman S, Yilmaz R, et al. The effects of maintenance recombinant human erythropoietin therapy on ambulatory blood pressure recordings: conventional, Doppler, and tissue Doppler echocardiographic parameters. Artif Organs 2005; 29:965–972.
  57. Fishbane S, Berns JS. Hemoglobin cycling in hemodialysis patients treated with recombinant human erythropoietin. Kidney Int 2005; 68:1337–1343.
  58. Szczech LA, Barnhart HX, Inrig JK, et al. Secondary analysis of the CHOIR trial epoetin-alpha dose and achieved hemoglobin outcomes. Kidney Int 2008; 74:791–798.
  59. Solomon SD, Uno H, Lewis EF, et al; Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) Investigators. Erythropoietic response and outcomes in kidney disease and type 2 diabetes. N Engl J Med 2010; 363:1146–1155.
  60. Kidney Disease: Improving Global Outcomes (KDIGO). KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney Int Suppl 2012; 2:279–335.
  61. Fernández-Rodríguez AM, Guindeo-Casasús MC, Molero-Labarta T, et al. Diagnosis of iron deficiency in chronic renal failure. Am J Kidney Dis 1999; 34:508–513.
  62. Eschbach JW, Cook JD, Scribner BH, Finch CA. Iron balance in hemodialysis patients. Ann Intern Med 1977; 87:710–713.
  63. Mittman N, Sreedhara R, Mushnick R, et al. Reticulocyte hemoglobin content predicts functional iron deficiency in hemodialysis patients receiving rHuEPO. Am J Kidney Dis 1997; 30:912–922.
  64. Tessitore N, Solero GP, Lippi G, et al. The role of iron status markers in predicting response to intravenous iron in haemodialysis patients on maintenance erythropoietin. Nephrol Dial Transplant 2001; 16:1416–1423.
  65. Coyne DW. Iron indices: what do they really mean? Kidney Int Suppl 2006; 101:S4–S8.
  66. Fishbane S, Kowalski EA, Imbriano LJ, Maesaka JK. The evaluation of iron status in hemodialysis patients. J Am Soc Nephrol 1996; 7:2654–2657.
  67. Coyne DW, Kapoian T, Suki W, et al; DRIVE Study Group. Ferric gluconate is highly efficacious in anemic hemodialysis patients with high serum ferritin and low transferrin saturation: results of the Dialysis Patients’ Response to IV Iron with Elevated Ferritin (DRIVE) Study. J Am Soc Nephrol 2007; 18:975–984.
  68. Radtke HW, Claussner A, Erbes PM, Scheuermann EH, Schoeppe W, Koch KM. Serum erythropoietin concentration in chronic renal failure: relationship to degree of anemia and excretory renal function. Blood 1979; 54:877–884.
  69. Korte W, Cogliatti SB, Jung K, Riesen W. Mild renal dysfunction is sufficient to induce erythropoietin deficiency in patients with unexplained anaemia. Clin Chim Acta 2000; 292:149–154.
  70. Locatelli F, Olivares J, Walker R, et al; European/Australian NESP 980202 Study Group. Novel erythropoiesis stimulating protein for treatment of anemia in chronic renal insufficiency. Kidney Int 2001; 60:741–747.
  71. Carrera F, Burnier M. Use of darbepoetin alfa in the treatment of anaemia of chronic kidney disease: clinical and pharmacoeconomic considerations. NDT Plus 2009; 2(suppl 1):i9–i17.
  72. Egrie JC, Browne JK. Development and characterization of novel erythropoiesis stimulating protein (NESP). Nephrol Dial Transplant 2001; 16(suppl 3):3–13.
  73. Nissenson AR, Charytan C. Controversies in iron management. Kidney Int Suppl 2003; 87:S64–S71.
  74. Kilpatrick RD, Critchlow CW, Fishbane S, et al. Greater epoetin alpha responsiveness is associated with improved survival in hemodialysis patients. Clin J Am Soc Nephrol 2008; 3:1077–1083.
  75. Locatelli F, Aljama P, Barany P, et al; European Best Practice Guidelines Working Group. Revised European best practice guidelines for the management of anaemia in patients with chronic renal failure. Nephrol Dial Transplant 2004; 19(suppl 2):ii1–ii47.
  76. Stenvinkel P. The role of inflammation in the anaemia of end-stage renal disease. Nephrol Dial Transplant 2001; 16(suppl 7):36–40.
  77. Barany P, Divino Filho JC, Bergstrom J. High C-reactive protein is a strong predictor of resistance to erythropoietin in hemodialysis patients. Am J Kidney Dis 1997; 29:565–568.
  78. Drueke T. Hyporesponsiveness to recombinant human erythropoietin. Nephrol Dial Transplant 2001; 16(suppl 7):25–28.
  79. Casadevall N. Cellular mechanism of resistance to erythropoietin. Nephrol Dial Transplant 1995; 10(suppl 6):27–30.
  80. Kraus E, Rabb H. EPO therapy during acute kidney disease: to use or not to use, that is the question. Am J Kidney Dis 2005; 46:967–969.
  81. Gotloib L, Silverberg D, Fudin R, Shostak A. Iron deficiency is a common cause of anemia in chronic kidney disease and can often be corrected with intravenous iron. J Nephrol 2006; 19:161–167.
  82. Tarng DC, Huang TP, Chen TW, Yang WC. Erythropoietin hyporesponsiveness: from iron deficiency to iron overload. Kidney Int Suppl 1999; 69:S107–S118.
  83. Drüeke TB. Modulating factors in the hematopoietic response to erythropoietin. Am J Kidney Dis 1991; 18(suppl 1):87–92.
  84. Boven K, Stryker S, Knight J, et al. The increased incidence of pure red cell aplasia with an Eprex formulation in uncoated rubber stopper syringes. Kidney Int 2005; 67:2346–2353.
  85. Shimizu H, Saitoh T, Ota F, et al. Pure red cell aplasia induced only by intravenous administration of recombinant human erythropoietin. Acta Haematol 2011; 126:114–118.
  86. Tonia T, Mettler A, Robert N, et al. Erythropoietin or darbepoetin for patients with cancer. Cochrane Database Syst Rev 2012; 12:CD003407.
  87. Bohlius J, Langensiepen S, Schwarzer G, et al. Recombinant human erythropoietin and overall survival in cancer patients: results of a comprehensive meta-analysis. J Natl Cancer Inst 2005; 97:489–498.
  88. Henke M, Laszig R, Rübe C, et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet 2003; 362:1255–1260.
  89. Leyland-Jones B, Semiglazov V, Pawlicki M, et al. Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study. J Clin Oncol 2005; 23:5960–5972.
  90. Brower V. Erythropoietin may impair, not improve, cancer survival. Nat Med 2003; 9:1439.
  91. Acs G, Acs P, Beckwith SM, et al. Erythropoietin and erythropoietin receptor expression in human cancer. Cancer Res 2001; 61:3561–3565.
  92. Yasuda Y, Fujita Y, Matsuo T, et al. Erythropoietin regulates tumour growth of human malignancies. Carcinogenesis 2003; 24:1021–1029.
  93. Levin NW, Fishbane S, Cañedo FV, et al; MAXIMA Study Investigators. Intravenous methoxy polyethylene glycol-epoetin beta for haemoglobin control in patients with chronic kidney disease who are on dialysis: a randomised non-inferiority trial (MAXIMA). Lancet 2007; 370:1415–1421.
  94. Macdougall IC, Walker R, Provenzano R, et al; ARCTOS Study Investigators. C.E.R.A. corrects anemia in patients with chronic kidney disease not on dialysis: results of a randomized clinical trial. Clin J Am Soc Nephrol 2008; 3:337–347.
  95. Frohna PA, Milwee S, Pinkett J, et al. Preliminary results from a randomized, single-blind, placebo-controlled trial of FG-4592, a novel hypoxia inducible factor prolyl hydroxylase inhibitor, in subjects with CKD anemia (abstract). J Am Soc Nephrol 2007; 18:763.
  96. Holdstock L, Meadowcroft AM, Maier R, et al. Four-week studies of oral hypoxia-inducible factor-prolyl hydroxylase inhibitor GSK1278863 for treatment of anemia. J Am Soc Nephrol 2016; 27:1234–1244.
Click for Credit Link
Article PDF
Author and Disclosure Information

Georges Nakhoul, MD
Department of Nephrology and Hypertension, Glickman Urological and Kidney institute, Cleveland Clinic

James F. Simon, MD
Department of Nephrology and Hypertension, Glickman Urological and Kidney institute, Cleveland Clinic; Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: James F. Simon, MD, Department of Nephrology and Hypertension, Q7, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; simonj2@ccf.org

Dr. Simon has disclosed membership on advisory committee or review panels and teaching and speaking for Alexion, and consulting for Regulus.

Issue
Cleveland Clinic Journal of Medicine - 83(8)
Publications
Topics
Page Number
613-624
Legacy Keywords
anemia, chronic kidney disease, erythropoietin, erythropoiesis-stimulating agents, ESAs, hypoxia-inducible factor, HIF, iron, Georges Nakhoul, James Simon
Sections
Click for Credit Link
Click for Credit Link
Author and Disclosure Information

Georges Nakhoul, MD
Department of Nephrology and Hypertension, Glickman Urological and Kidney institute, Cleveland Clinic

James F. Simon, MD
Department of Nephrology and Hypertension, Glickman Urological and Kidney institute, Cleveland Clinic; Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: James F. Simon, MD, Department of Nephrology and Hypertension, Q7, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; simonj2@ccf.org

Dr. Simon has disclosed membership on advisory committee or review panels and teaching and speaking for Alexion, and consulting for Regulus.

Author and Disclosure Information

Georges Nakhoul, MD
Department of Nephrology and Hypertension, Glickman Urological and Kidney institute, Cleveland Clinic

James F. Simon, MD
Department of Nephrology and Hypertension, Glickman Urological and Kidney institute, Cleveland Clinic; Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: James F. Simon, MD, Department of Nephrology and Hypertension, Q7, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; simonj2@ccf.org

Dr. Simon has disclosed membership on advisory committee or review panels and teaching and speaking for Alexion, and consulting for Regulus.

Article PDF
Article PDF
Related Articles

Anemia is a frequent complication of chronic kidney disease, occurring in over 90% of patients receiving renal replacement therapy. It is associated with significant morbidity and mortality. While its pathogenesis is typically multifactorial, the predominant cause is failure of the kidneys to produce enough endogenous erythropoietin. The clinical approval of recombinant human erythropoietin in 1989 dramatically changed the treatment of anemia of chronic kidney disease, but randomized controlled trials yielded disappointing results when erythropoiesis-stimulating agents (ESAs) were used to raise hemoglobin to normal levels.

This article reviews the epidemiology and pathophysiology of anemia of chronic kidney disease and discusses the complicated and conflicting evidence regarding its treatment.

DEFINITION AND PREVALENCE

Anemia is defined as a hemoglobin concentration less than 13.0 g/dL for men and less than 12.0 g/dL for premenopausal women.1 It is more common in patients with impaired kidney function, especially when the glomerular filtration rate (GFR) falls below 60 mL/min. It is rare at GFRs higher than 80 mL/min,2 but as the GFR falls, the severity of the anemia worsens3 and its prevalence increases: almost 90% of patients with a GFR less than 30 mL/min are anemic.4

RENAL ANEMIA IS ASSOCIATED WITH BAD OUTCOMES

Anemia in chronic kidney disease is independently associated with risk of death. It is also an all-cause mortality multiplier, ie, it magnifies the risk of death from other disease states.5

In observational studies, anemia was associated with faster progression of left ventricular hypertrophy, inflammation, and increased myocardial and peripheral oxygen demand, thereby leading to worse cardiac outcomes with increased risk of myocardial infarction, coronary revascularization, and readmission for heart failure.6–8 Anemia is also associated with fatigue, depression, reduced exercise tolerance, stroke, and increased risk of rehospitalization.9–13

RENAL ANEMIA IS MULTIFACTORIAL

Anemia of chronic kidney disease is typically attributed to the decrease of erythropoietin production that accompanies the fall in GFR. However, the process is multifactorial, with several other contributing factors: absolute and functional iron deficiency, folate and vitamin B12 deficiencies, reduced red blood cell life span, and suppression of erythropoiesis by the uremic milieu.14

While it was once thought that chronic kidney disease leads to loss of erythropoietin-producing cells, it is now known that downregulation of hypoxia-inducible factor (HIF; a transcription factor) is at least partially responsible for the decrease in erythropoietin production15,16 and that this downregulation is reversible (see below).

ERYTHROPOIETIN, IRON, AND RED BLOOD CELLS

Erythropoietin production is triggered by hypoxia, mediated by HIF

Erythropoietin is produced primarily in the deep cortex and outer medulla of the kidneys by a special population of peritubular interstitial cells.17 The parenchymal cells of the liver also produce erythropoietin, but much less.18

Figure 1.

The rate of renal erythropoietin synthesis is determined by tissue oxygenation rather than by renal blood flow; production increases as the hemoglobin concentration drops and the arterial oxygen tension decreases (Figure 1).19

The gene for erythropoietin is located on chromosome 7 and is regulated by HIF. HIF molecules are composed of an alpha subunit, which is unstable at high Po2, and a beta subunit, constitutively present in the nucleus.20

In hypoxic conditions, the HIF dimer is transcriptionally active and binds to specific DNA recognition sequences called hypoxia-response elements. Gene transcription is upregulated, leading to increased production of erythropoietin.21

Under normal oxygen tension, on the other hand, the proline residue of the HIF alpha subunit is hydroxylated. The hydroxylated HIF alpha subunit is then degraded by proteasomal ubiquitylation, which is mediated by the von Hippel-Lindau tumor-suppressor gene pVHL.22 Degradation of HIF alpha prevents formation of the HIF heterodimers. HIF therefore cannot bind to the hypoxia-response elements, and erythropoietin gene transcription does not occur.23

Thus, in states of hypoxia, erythropoietin production is upregulated, whereas with normal oxygen tension, production is downregulated.

Erythropoietin is essential for terminal maturation of erythrocytes

Erythropoietin is essential for terminal maturation of erythrocytes.24 It is thought to stimulate the growth of erythrogenic progenitors: burst-forming units-erythroid (BFU-E) and colony-forming units-erythroid (CFU-E). In the absence of erythropoietin, BFU-E and CFU-E fail to differentiate into mature erythrocytes.25

Binding of erythropoietin to its receptor sets off a series of downstream signals, the most important being the signal transducer and activator of transcription 5 (STAT5). In animal studies, STAT5 was found to inhibit apoptosis through the early induction of an antiapoptotic gene, Bcl-xL.26

Iron metabolism is controlled by several proteins

Iron is characterized by its capacity to accept or donate electrons. This unique property makes it a crucial element in many biochemical reactions such as enzymatic activity, DNA synthesis, oxygen transport, and cell respiration.

Figure 2. Iron absorption and metabolism is controlled by several proteins. DMT1 = divalent metal transporter 1; FPN = ferroportin; Hgb = hemoglobin; TF = transferrin, TFR = transferrin receptor

Iron metabolism is under the control of several proteins that play different roles in its absorption, recycling, and loss (Figure 2).27

Dietary iron exists primarily in its poorly soluble trivalent ferric form (Fe3+), and it needs to be reduced to its soluble divalent ferrous form (Fe2+) by ferric reductase to be absorbed. Ferrous iron is taken up at the apical side of enterocytes by a divalent metal transporter (DMT1) and is transported across the brush border.28

To enter the circulation, iron has to be transported across the basolateral membrane by a transporter called ferroportin.29 Ferroportin is also found in placental syncitiotrophoblasts, where it transfers iron from mother to fetus, and in macrophages, where it allows recycling of iron scavenged from damaged cells back into the circulation.30 Upon its release, the ferrous iron is oxidized to the ferric form and loaded onto transferrin. This oxidation process involves hephaestin, a homologue of the ferroxidase ceruloplasmin.31

In the plasma, iron is bound to transferrin, and under normal circumstances one-third of transferrin is saturated with iron.32 Transferrin receptors are present on most cells but are most dense on erythroid precursors. Each transferrin receptor can bind two transferrin molecules. After binding to transferrin, the transferrin receptor is endocytosed, and the iron is released into acidified vacuoles. The transferrin-receptor complex is then recycled to the surface.33

Ferritin is the cellular storage protein for iron, and it can store up to 4,500 atoms of iron within its spherical cavity.34 The serum level of ferritin reflects overall storage, with 1 ng/mL of ferritin indicating 10 mg of total iron stores.35 Ferritin is also an acute-phase reactant, and plasma levels can increase in inflammatory states such as infection or malignancy. As such, elevated ferritin does not necessarily indicate elevated iron stores.

Iron is lost in sweat, shed skin cells, and sloughed intestinal mucosal cells. However, there is no specific mechanism of iron excretion from the human body. Thus, iron is mainly regulated at the level of intestinal absorption. The iron exporter ferroportin is upregulated by the amount of available iron and is degraded by hepcidin.36

Hepcidin is a small cysteine-rich cationic peptide that is primarily produced in the liver, with some minor production also occurring in the kidneys.37 Transcription of the gene encoding hepcidin is downregulated by anemia and hypoxia and upregulated by inflammation and elevated iron levels.38 Transcription of hepcidin leads to degradation of ferroportin and a decrease in intestinal iron absorption. On the other hand, anemia and hypoxia inhibit hepcidin transcription, which allows ferroportin to facilitate intestinal iron absorption.

TREATMENT OF RENAL ANEMIA

Early enthusiasm for erythropoietin agents

Androgens started to be used to treat anemia of end-stage renal disease in 1970,39,40 and before the advent of recombinant human erythropoietin, they were a mainstay of nontransfusional therapy for anemic patients on dialysis.

The approval of recombinant human erythropoietin in 1989 drastically shifted the treatment of renal anemia. While the initial goal of treating anemia of chronic kidney disease with erythropoietin was to prevent blood transfusions,41 subsequent studies showed that the benefits might be far greater. Indeed, an initial observational trial showed that erythropoiesis-stimulating agents (ESAs) were associated with improved quality of life,42 improved neurocognitive function,43,44 and even cost savings.45 The benefits also extended to major outcomes such as regression of left ventricular hypertrophy,46 improvement in New York Heart Association class and cardiac function,47 fewer hospitalizations,48 and even reduction of cardiovascular mortality rates.49

As a result, ESA use gained popularity, and by 2006 an estimated 90% of dialysis patients were receiving these agents.50 The target and achieved hemoglobin levels also increased, with mean hemoglobin levels in hemodialysis patients being raised from 9.7 to 12 g/dL.51

Disappointing results in clinical trials of ESAs to normalize hemoglobin

To prospectively study the effects of normalized hemoglobin targets, four randomized controlled trials were conducted (Table 1):

  • The Normal Hematocrit Study (NHCT)52
  • The Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial53
  • The Cardiovascular Risk Reduction by Early Anemia Treatment (CREATE) trial54
  • The Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT).55

These trials randomized patients to either higher “normal-range” hemoglobin targets or to lower target hemoglobin levels.

Their findings were disappointing and raised several red flags about excessive use of ESAs. The trials found no benefit in higher hemoglobin targets, and in fact, some of them demonstrated harm in patients randomized to higher targets. Notably, higher hemoglobin targets were associated with significant side effects such as access-site  thrombosis,52 strokes,55 and possibly cardiovascular events.54,55 Only the CREATE trial was able to demonstrate a quality-of-life benefit for the high-target group.54 

It remains unclear whether these adverse events were from the therapy itself or from an increased morbidity burden in the treated patients. Erythropoietin use is associated with hypertension,56 thought to be related to endothelin-mediated vasoconstriction.57 In our experience, this is most evident when hemoglobin levels are normalized with ESA therapy. Cycling of erythropoietin levels between extreme levels can lead to vascular remodeling, which may also be related to its cardiovascular effects.57

A noticeable finding in several of these trials was that patients failed to achieve the higher hemoglobin target despite the use of very high doses of ESA. Reanalysis of data from the CHOIR and CREATE trials showed that the patients who had worse outcomes were more likely to have required very high doses without achieving their target hemoglobin.58,59 Indeed, patients who achieved the higher target hemoglobin levels, usually at lower ESA doses, had better outcomes. This suggested that the need for a higher dose was associated with poorer outcomes, either as a marker of comorbidity or due to yet undocumented side effects of such high doses.

General approach to therapy

Before attributing anemia to chronic kidney disease, a thorough evaluation should be conducted to look for any reversible process that could be contributing to the anemia.

The causes of anemia are numerous and beyond the scope of this review. However, among the common causes of anemia in chronic kidney disease are deficiencies of iron, vitamin B12, and folate. Therefore, guidelines recommend checking iron, vitamin B12, and folate levels in the initial evaluation of anemia.60

Iron deficiency in particular is very common in chronic kidney disease patients and is present in nearly all dialysis patients.61 Hemodialysis patients are estimated to lose 1 to 3 g of iron per year as a result of blood loss in the dialysis circuit and increased iron utilization secondary to ESA therapy.62

However, in contrast to the general population, in which the upper limits of normal for iron indices are well defined, high serum ferritin levels appear to be poorly predictive of hemoglobin responsiveness in dialysis patients.63,64 Thus, the cutoffs that define iron responsiveness are much higher than standard definitions for iron deficiency.65,66 The Dialysis Patients’ Response to IV Iron With Elevated Ferritin (DRIVE) study showed that dialysis patients benefit from intravenous iron therapy even if their ferritin is as high as 1,200 ng/mL, provided their transferrin saturation is below 30%.67

Of note, erythropoietin levels cannot be used to distinguish renal anemia from other causes of anemia. Indeed, patients with renal failure may have “relative erythropoietin deficiency,” ie, “normal” erythropoietin levels that are actually too low in view of the degree of anemia.68,69 In addition to the decreased production capacity by the kidney, there appears to be a component of resistance to the action of erythropoietin in the bone marrow.

For these reasons, there is no erythropoietin level that can be considered “inadequate” or defining of renal anemia. Thus, measuring erythropoietin levels is not routinely recommended in the evaluation of renal anemia.

 

 

Two ESA preparations

The two ESAs that have traditionally been used in the treatment of renal anemia are recombinant human erythropoietin and darbepoietin alfa. They appear to be equivalent in terms of safety and efficacy.70 However, darbepoietin alfa has more sialic acid molecules, giving it a higher potency and longer half-life and allowing for less-frequent injections.71,72

In nondialysis patients, recombinant human erythropoietin is typically given every 1 to 2 weeks, whereas darbepoietin alfa can be given every 2 to 4 weeks. In dialysis patients, recombinant human erythropoietin is typically given 3 times per week with every dialysis treatment, while darbepoietin alfa is given once a week.

Target hemoglobin levels: ≤ 11.5 g/dL

In light of the four trials described in Table 1, the international Kidney Disease: Improving Global Outcomes (KDIGO) guidelines60 recommend the following (Table 2):

For patients with chronic kidney disease who are not on dialysis, ESA therapy should not be initiated if the hemoglobin level is higher than 10 g/dL. If the hemoglobin level is lower than 10 g/dL, ESA therapy can be initiated, but the decision needs to be individualized based on the rate of fall of hemoglobin concentration, prior response to iron therapy, the risk of needing a transfusion, the risks related to ESA therapy, and the presence of symptoms attributable to anemia.

For patients on dialysis, ESA therapy should be used when the hemoglobin level is between 9 and 10 g/dL to avoid having the hemoglobin fall below 9 g/dL.

In all adult patients, ESAs should not be used to intentionally increase the hemoglobin level above 13 g/dL but rather to maintain levels no higher than 11.5 g/dL. This target is based on the observation that adverse outcomes were associated with ESA use with hemoglobin targets higher than 13 g/dL (Table 1).

Target iron levels

Regarding iron stores, the guidelines recommend the following:

For adult patients with chronic kidney disease who are not on dialysis, iron should be given to keep transferrin saturation above 20% and ferritin above 100 ng/mL. Transferrin saturation should not exceed 30%, and ferritin levels should not exceed 500 ng/mL.

For adult patients on dialysis, iron should be given to maintain transferrin saturation above 30% and ferritin above 200 ng/mL.

The upper limits of ferritin and transferrin saturation are somewhat controversial, as the safety of intentionally maintaining respective levels greater than 30% and 500 ng/mL has been studied in very few patients. Transferrin saturation should in general not exceed 50%.

High ferritin levels are associated with higher death rates, but whether elevation of ferritin levels is a marker of excessive iron administration rather than a nonspecific acute-phase reactant is not clear. The 2006 guidelines60 cited upper ferritin limits of 500 to 800 ng/mL. However, the more recent DRIVE trial67 showed that patients with ferritin levels of 500 to 1,200 ng/mL will respond to intravenous administration of iron with an increase in their hemoglobin levels. This has led many clinicians to adopt a higher ferritin limit of 1,200 ng/mL.

Hemosiderosis, or excess iron deposition, was a known consequence of frequent transfusions in patients with end-stage renal disease before ESA therapy was available. However, there have been no documented cases of clinical iron overload from iron therapy using current guidelines.73

These algorithms are nuanced, and the benefit of giving intravenous iron should always be weighed against the risks of short-term acute toxicity and infection. Treatment of renal anemia not only requires in-depth knowledge of the topic, but also familiarity with the patient’s specific situation. As such, it is not recommended that clinicians unfamiliar with the treatment of renal anemia manage its treatment.

PARTICULAR CIRCUMSTANCES

Inflammation and ESA resistance

While ESAs are effective in treating anemia in many cases, in many patients the anemia fails to respond. This is of particular importance, since ESA hyporesponsiveness has been found to be a powerful predictor of cardiovascular events and death.74 It is unclear, however, whether high doses of ESA are inherently toxic or whether hyporesponsiveness is a marker of adverse outcomes related to comorbidities.

KDIGO defines initial hyporesponsiveness as having no increase in hemoglobin concentration after the first month of appropriate weight-based dosing, and acquired hyporesponsiveness as requiring two increases in ESA doses up to 50% beyond the dose at which the patient had originally been stable.60 Identifying ESA hyporesponsiveness should lead to an intensive search for potentially correctable factors.

The two major factors accounting for the state of hyporesponsiveness are inflammation and iron deficiency.75,76

Inflammation. High C-reactive protein levels have been shown to predict resistance to erythropoietin in dialysis patients.77 The release of cytokines such as tumor necrosis factor alpha, interleukin 1, and interferon gamma has an inhibitory effect on erythropoiesis.78 Additionally, inflammation can alter the response to ESAs by disrupting the metabolism of iron79 through the release of hepcidin, as previously discussed.38 These reasons likely account for the observed lower response to ESAs in the setting of acute illness and explain why ESAs are not recommended for correcting acute anemia.80

Iron deficiency also can blunt the response to ESAs. Large amounts of iron are needed for effective erythropoietic bursts. As such, iron supplementation is now a recognized treatment of renal anemia.81

Other factors associated with hyporesponsiveness include chronic occult blood loss, aluminum toxicity, cobalamin or folate deficiencies, testosterone deficiency, inadequate dialysis, hyperparathyroidism, and superimposed primary bone marrow disease,82,83 and these should be addressed in patients whose anemia does not respond as expected to ESA therapy. A summary of the main causes of ESA hyporesponsiveness, their reversibility, and recommended treatments is presented in Table 3.

Antibody-mediated pure red-cell aplasia. Rarely, patients receiving ESA therapy develop antibodies that neutralize both the ESA and endogenous erythropoietin. The resulting syndrome, called antibody-mediated pure red-cell aplasia, is characterized by the sudden development of severe transfusion-dependent anemia. This has historically been connected to epoetin beta, a formulation not in use in the United States. However, cases have been documented with epoetin alfa and darbepoetin. The incidence rate is low with subcutaneous ESA use, estimated at 0.5 cases per 10,000 patient-years84 and anecdotal with intravenous ESA.85 The definitive diagnosis requires demonstration of neutralizing antibodies against erythropoietin. Parvovirus infection should be excluded as an alternative cause of pure red­cell aplasia.

ANEMIA IN CANCER PATIENTS

ESAs are effective in raising hemoglobin levels and reducing transfusion requirements in patients with chemotherapy-induced anemia.86 However, there are data linking the use of ESAs to shortened survival in patients who have a variety of solid tumors.87

Several mechanisms have been proposed to explain this rapid disease progression, most notably acceleration in tumor growth88–90 by stimulation of erythropoietin receptors on the surface of the tumor cells, leading to increased tumor angiogenesis.91,92

For these reasons, treatment of renal anemia in the setting of active malignancy should be referred to an oncologist.

NOVEL TREATMENTS

Several new agents for treating renal anemia are currently under review.

Continuous erythropoiesis receptor activator

Continuous erythropoiesis receptor activator is a pegylated form of recombinant human erythropoietin that has the ability to repeatedly activate the erythropoietin receptor. It appears to be similar to the other forms of erythropoietin in terms of safety and efficacy in both end-stage renal disease93 and chronic kidney disease.94 It has the advantage of an extended serum half-life, which allows for longer dosing intervals, ie, every 2 weeks. Its use is currently gaining popularity in the dialysis community.

HIF stabilizers

Our growing understanding of the physiology of erythropoietin offers new potential treatment targets. As previously described, production of erythropoietin is stimulated by HIFs. In order to be degraded, these HIFs are hydroxylated at their proline residues by a prolyl hydroxylase. A new category of drugs called prolyl-hydroxylase inhibitors (PDIs) offers the advantage of stabilizing the HIFs, leading to an increase in erythropoietin production.

In phase 1 and 2 clinical trials, these agents have been shown to increase hemoglobin in both end-stage renal disease and chronic kidney disease patients15,16 but not in anephric patients, demonstrating a renal source of the erythropoietin production even in nonfunctioning kidneys. The study of one PDI agent (FG 2216) was halted temporarily after a report of death from fulminant hepatitis, but the other (FG 4592) continues to be studied in a phase 2 clinical trial.95,96

TAKE-HOME POINTS

  • Anemia of renal disease is a common condition that is mainly caused by a decrease in erythropoietin production by the kidneys.
  • While anemia of renal disease can be corrected with ESAs, it is necessary to investigate and rule out underlying treatable conditions such as iron or vitamin deficiencies before giving an ESA.
  • Anemia of renal disease is associated with significant morbidity such as increased risk of left ventricular hypertrophy, myocardial infarction, and heart failure, and has been described as an all-cause mortality multiplier.
  • Unfortunately, the only undisputed benefit of treatment to date remains the avoidance of blood transfusions. Furthermore, the large randomized controlled trials that looked at the benefits of ESA have shown that their use can be associated with increased risk of cardiovascular events. Therefore, use of an ESA in end-stage renal disease should never target a normal hemoglobin levels but rather aim for a hemoglobin level of no more than 11.5 g/dL.
  • Use of an ESA in chronic kidney disease should be individualized and is not recommended to be started unless the hemoglobin level is less than 10 g/dL.
  • Several newer agents for renal anemia are currently under review. A pegylated form of recombinant human erythropoietin has an extended half-life, and a new and promising category of drugs called HIF stabilizers is currently under study.

Anemia is a frequent complication of chronic kidney disease, occurring in over 90% of patients receiving renal replacement therapy. It is associated with significant morbidity and mortality. While its pathogenesis is typically multifactorial, the predominant cause is failure of the kidneys to produce enough endogenous erythropoietin. The clinical approval of recombinant human erythropoietin in 1989 dramatically changed the treatment of anemia of chronic kidney disease, but randomized controlled trials yielded disappointing results when erythropoiesis-stimulating agents (ESAs) were used to raise hemoglobin to normal levels.

This article reviews the epidemiology and pathophysiology of anemia of chronic kidney disease and discusses the complicated and conflicting evidence regarding its treatment.

DEFINITION AND PREVALENCE

Anemia is defined as a hemoglobin concentration less than 13.0 g/dL for men and less than 12.0 g/dL for premenopausal women.1 It is more common in patients with impaired kidney function, especially when the glomerular filtration rate (GFR) falls below 60 mL/min. It is rare at GFRs higher than 80 mL/min,2 but as the GFR falls, the severity of the anemia worsens3 and its prevalence increases: almost 90% of patients with a GFR less than 30 mL/min are anemic.4

RENAL ANEMIA IS ASSOCIATED WITH BAD OUTCOMES

Anemia in chronic kidney disease is independently associated with risk of death. It is also an all-cause mortality multiplier, ie, it magnifies the risk of death from other disease states.5

In observational studies, anemia was associated with faster progression of left ventricular hypertrophy, inflammation, and increased myocardial and peripheral oxygen demand, thereby leading to worse cardiac outcomes with increased risk of myocardial infarction, coronary revascularization, and readmission for heart failure.6–8 Anemia is also associated with fatigue, depression, reduced exercise tolerance, stroke, and increased risk of rehospitalization.9–13

RENAL ANEMIA IS MULTIFACTORIAL

Anemia of chronic kidney disease is typically attributed to the decrease of erythropoietin production that accompanies the fall in GFR. However, the process is multifactorial, with several other contributing factors: absolute and functional iron deficiency, folate and vitamin B12 deficiencies, reduced red blood cell life span, and suppression of erythropoiesis by the uremic milieu.14

While it was once thought that chronic kidney disease leads to loss of erythropoietin-producing cells, it is now known that downregulation of hypoxia-inducible factor (HIF; a transcription factor) is at least partially responsible for the decrease in erythropoietin production15,16 and that this downregulation is reversible (see below).

ERYTHROPOIETIN, IRON, AND RED BLOOD CELLS

Erythropoietin production is triggered by hypoxia, mediated by HIF

Erythropoietin is produced primarily in the deep cortex and outer medulla of the kidneys by a special population of peritubular interstitial cells.17 The parenchymal cells of the liver also produce erythropoietin, but much less.18

Figure 1.

The rate of renal erythropoietin synthesis is determined by tissue oxygenation rather than by renal blood flow; production increases as the hemoglobin concentration drops and the arterial oxygen tension decreases (Figure 1).19

The gene for erythropoietin is located on chromosome 7 and is regulated by HIF. HIF molecules are composed of an alpha subunit, which is unstable at high Po2, and a beta subunit, constitutively present in the nucleus.20

In hypoxic conditions, the HIF dimer is transcriptionally active and binds to specific DNA recognition sequences called hypoxia-response elements. Gene transcription is upregulated, leading to increased production of erythropoietin.21

Under normal oxygen tension, on the other hand, the proline residue of the HIF alpha subunit is hydroxylated. The hydroxylated HIF alpha subunit is then degraded by proteasomal ubiquitylation, which is mediated by the von Hippel-Lindau tumor-suppressor gene pVHL.22 Degradation of HIF alpha prevents formation of the HIF heterodimers. HIF therefore cannot bind to the hypoxia-response elements, and erythropoietin gene transcription does not occur.23

Thus, in states of hypoxia, erythropoietin production is upregulated, whereas with normal oxygen tension, production is downregulated.

Erythropoietin is essential for terminal maturation of erythrocytes

Erythropoietin is essential for terminal maturation of erythrocytes.24 It is thought to stimulate the growth of erythrogenic progenitors: burst-forming units-erythroid (BFU-E) and colony-forming units-erythroid (CFU-E). In the absence of erythropoietin, BFU-E and CFU-E fail to differentiate into mature erythrocytes.25

Binding of erythropoietin to its receptor sets off a series of downstream signals, the most important being the signal transducer and activator of transcription 5 (STAT5). In animal studies, STAT5 was found to inhibit apoptosis through the early induction of an antiapoptotic gene, Bcl-xL.26

Iron metabolism is controlled by several proteins

Iron is characterized by its capacity to accept or donate electrons. This unique property makes it a crucial element in many biochemical reactions such as enzymatic activity, DNA synthesis, oxygen transport, and cell respiration.

Figure 2. Iron absorption and metabolism is controlled by several proteins. DMT1 = divalent metal transporter 1; FPN = ferroportin; Hgb = hemoglobin; TF = transferrin, TFR = transferrin receptor

Iron metabolism is under the control of several proteins that play different roles in its absorption, recycling, and loss (Figure 2).27

Dietary iron exists primarily in its poorly soluble trivalent ferric form (Fe3+), and it needs to be reduced to its soluble divalent ferrous form (Fe2+) by ferric reductase to be absorbed. Ferrous iron is taken up at the apical side of enterocytes by a divalent metal transporter (DMT1) and is transported across the brush border.28

To enter the circulation, iron has to be transported across the basolateral membrane by a transporter called ferroportin.29 Ferroportin is also found in placental syncitiotrophoblasts, where it transfers iron from mother to fetus, and in macrophages, where it allows recycling of iron scavenged from damaged cells back into the circulation.30 Upon its release, the ferrous iron is oxidized to the ferric form and loaded onto transferrin. This oxidation process involves hephaestin, a homologue of the ferroxidase ceruloplasmin.31

In the plasma, iron is bound to transferrin, and under normal circumstances one-third of transferrin is saturated with iron.32 Transferrin receptors are present on most cells but are most dense on erythroid precursors. Each transferrin receptor can bind two transferrin molecules. After binding to transferrin, the transferrin receptor is endocytosed, and the iron is released into acidified vacuoles. The transferrin-receptor complex is then recycled to the surface.33

Ferritin is the cellular storage protein for iron, and it can store up to 4,500 atoms of iron within its spherical cavity.34 The serum level of ferritin reflects overall storage, with 1 ng/mL of ferritin indicating 10 mg of total iron stores.35 Ferritin is also an acute-phase reactant, and plasma levels can increase in inflammatory states such as infection or malignancy. As such, elevated ferritin does not necessarily indicate elevated iron stores.

Iron is lost in sweat, shed skin cells, and sloughed intestinal mucosal cells. However, there is no specific mechanism of iron excretion from the human body. Thus, iron is mainly regulated at the level of intestinal absorption. The iron exporter ferroportin is upregulated by the amount of available iron and is degraded by hepcidin.36

Hepcidin is a small cysteine-rich cationic peptide that is primarily produced in the liver, with some minor production also occurring in the kidneys.37 Transcription of the gene encoding hepcidin is downregulated by anemia and hypoxia and upregulated by inflammation and elevated iron levels.38 Transcription of hepcidin leads to degradation of ferroportin and a decrease in intestinal iron absorption. On the other hand, anemia and hypoxia inhibit hepcidin transcription, which allows ferroportin to facilitate intestinal iron absorption.

TREATMENT OF RENAL ANEMIA

Early enthusiasm for erythropoietin agents

Androgens started to be used to treat anemia of end-stage renal disease in 1970,39,40 and before the advent of recombinant human erythropoietin, they were a mainstay of nontransfusional therapy for anemic patients on dialysis.

The approval of recombinant human erythropoietin in 1989 drastically shifted the treatment of renal anemia. While the initial goal of treating anemia of chronic kidney disease with erythropoietin was to prevent blood transfusions,41 subsequent studies showed that the benefits might be far greater. Indeed, an initial observational trial showed that erythropoiesis-stimulating agents (ESAs) were associated with improved quality of life,42 improved neurocognitive function,43,44 and even cost savings.45 The benefits also extended to major outcomes such as regression of left ventricular hypertrophy,46 improvement in New York Heart Association class and cardiac function,47 fewer hospitalizations,48 and even reduction of cardiovascular mortality rates.49

As a result, ESA use gained popularity, and by 2006 an estimated 90% of dialysis patients were receiving these agents.50 The target and achieved hemoglobin levels also increased, with mean hemoglobin levels in hemodialysis patients being raised from 9.7 to 12 g/dL.51

Disappointing results in clinical trials of ESAs to normalize hemoglobin

To prospectively study the effects of normalized hemoglobin targets, four randomized controlled trials were conducted (Table 1):

  • The Normal Hematocrit Study (NHCT)52
  • The Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial53
  • The Cardiovascular Risk Reduction by Early Anemia Treatment (CREATE) trial54
  • The Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT).55

These trials randomized patients to either higher “normal-range” hemoglobin targets or to lower target hemoglobin levels.

Their findings were disappointing and raised several red flags about excessive use of ESAs. The trials found no benefit in higher hemoglobin targets, and in fact, some of them demonstrated harm in patients randomized to higher targets. Notably, higher hemoglobin targets were associated with significant side effects such as access-site  thrombosis,52 strokes,55 and possibly cardiovascular events.54,55 Only the CREATE trial was able to demonstrate a quality-of-life benefit for the high-target group.54 

It remains unclear whether these adverse events were from the therapy itself or from an increased morbidity burden in the treated patients. Erythropoietin use is associated with hypertension,56 thought to be related to endothelin-mediated vasoconstriction.57 In our experience, this is most evident when hemoglobin levels are normalized with ESA therapy. Cycling of erythropoietin levels between extreme levels can lead to vascular remodeling, which may also be related to its cardiovascular effects.57

A noticeable finding in several of these trials was that patients failed to achieve the higher hemoglobin target despite the use of very high doses of ESA. Reanalysis of data from the CHOIR and CREATE trials showed that the patients who had worse outcomes were more likely to have required very high doses without achieving their target hemoglobin.58,59 Indeed, patients who achieved the higher target hemoglobin levels, usually at lower ESA doses, had better outcomes. This suggested that the need for a higher dose was associated with poorer outcomes, either as a marker of comorbidity or due to yet undocumented side effects of such high doses.

General approach to therapy

Before attributing anemia to chronic kidney disease, a thorough evaluation should be conducted to look for any reversible process that could be contributing to the anemia.

The causes of anemia are numerous and beyond the scope of this review. However, among the common causes of anemia in chronic kidney disease are deficiencies of iron, vitamin B12, and folate. Therefore, guidelines recommend checking iron, vitamin B12, and folate levels in the initial evaluation of anemia.60

Iron deficiency in particular is very common in chronic kidney disease patients and is present in nearly all dialysis patients.61 Hemodialysis patients are estimated to lose 1 to 3 g of iron per year as a result of blood loss in the dialysis circuit and increased iron utilization secondary to ESA therapy.62

However, in contrast to the general population, in which the upper limits of normal for iron indices are well defined, high serum ferritin levels appear to be poorly predictive of hemoglobin responsiveness in dialysis patients.63,64 Thus, the cutoffs that define iron responsiveness are much higher than standard definitions for iron deficiency.65,66 The Dialysis Patients’ Response to IV Iron With Elevated Ferritin (DRIVE) study showed that dialysis patients benefit from intravenous iron therapy even if their ferritin is as high as 1,200 ng/mL, provided their transferrin saturation is below 30%.67

Of note, erythropoietin levels cannot be used to distinguish renal anemia from other causes of anemia. Indeed, patients with renal failure may have “relative erythropoietin deficiency,” ie, “normal” erythropoietin levels that are actually too low in view of the degree of anemia.68,69 In addition to the decreased production capacity by the kidney, there appears to be a component of resistance to the action of erythropoietin in the bone marrow.

For these reasons, there is no erythropoietin level that can be considered “inadequate” or defining of renal anemia. Thus, measuring erythropoietin levels is not routinely recommended in the evaluation of renal anemia.

 

 

Two ESA preparations

The two ESAs that have traditionally been used in the treatment of renal anemia are recombinant human erythropoietin and darbepoietin alfa. They appear to be equivalent in terms of safety and efficacy.70 However, darbepoietin alfa has more sialic acid molecules, giving it a higher potency and longer half-life and allowing for less-frequent injections.71,72

In nondialysis patients, recombinant human erythropoietin is typically given every 1 to 2 weeks, whereas darbepoietin alfa can be given every 2 to 4 weeks. In dialysis patients, recombinant human erythropoietin is typically given 3 times per week with every dialysis treatment, while darbepoietin alfa is given once a week.

Target hemoglobin levels: ≤ 11.5 g/dL

In light of the four trials described in Table 1, the international Kidney Disease: Improving Global Outcomes (KDIGO) guidelines60 recommend the following (Table 2):

For patients with chronic kidney disease who are not on dialysis, ESA therapy should not be initiated if the hemoglobin level is higher than 10 g/dL. If the hemoglobin level is lower than 10 g/dL, ESA therapy can be initiated, but the decision needs to be individualized based on the rate of fall of hemoglobin concentration, prior response to iron therapy, the risk of needing a transfusion, the risks related to ESA therapy, and the presence of symptoms attributable to anemia.

For patients on dialysis, ESA therapy should be used when the hemoglobin level is between 9 and 10 g/dL to avoid having the hemoglobin fall below 9 g/dL.

In all adult patients, ESAs should not be used to intentionally increase the hemoglobin level above 13 g/dL but rather to maintain levels no higher than 11.5 g/dL. This target is based on the observation that adverse outcomes were associated with ESA use with hemoglobin targets higher than 13 g/dL (Table 1).

Target iron levels

Regarding iron stores, the guidelines recommend the following:

For adult patients with chronic kidney disease who are not on dialysis, iron should be given to keep transferrin saturation above 20% and ferritin above 100 ng/mL. Transferrin saturation should not exceed 30%, and ferritin levels should not exceed 500 ng/mL.

For adult patients on dialysis, iron should be given to maintain transferrin saturation above 30% and ferritin above 200 ng/mL.

The upper limits of ferritin and transferrin saturation are somewhat controversial, as the safety of intentionally maintaining respective levels greater than 30% and 500 ng/mL has been studied in very few patients. Transferrin saturation should in general not exceed 50%.

High ferritin levels are associated with higher death rates, but whether elevation of ferritin levels is a marker of excessive iron administration rather than a nonspecific acute-phase reactant is not clear. The 2006 guidelines60 cited upper ferritin limits of 500 to 800 ng/mL. However, the more recent DRIVE trial67 showed that patients with ferritin levels of 500 to 1,200 ng/mL will respond to intravenous administration of iron with an increase in their hemoglobin levels. This has led many clinicians to adopt a higher ferritin limit of 1,200 ng/mL.

Hemosiderosis, or excess iron deposition, was a known consequence of frequent transfusions in patients with end-stage renal disease before ESA therapy was available. However, there have been no documented cases of clinical iron overload from iron therapy using current guidelines.73

These algorithms are nuanced, and the benefit of giving intravenous iron should always be weighed against the risks of short-term acute toxicity and infection. Treatment of renal anemia not only requires in-depth knowledge of the topic, but also familiarity with the patient’s specific situation. As such, it is not recommended that clinicians unfamiliar with the treatment of renal anemia manage its treatment.

PARTICULAR CIRCUMSTANCES

Inflammation and ESA resistance

While ESAs are effective in treating anemia in many cases, in many patients the anemia fails to respond. This is of particular importance, since ESA hyporesponsiveness has been found to be a powerful predictor of cardiovascular events and death.74 It is unclear, however, whether high doses of ESA are inherently toxic or whether hyporesponsiveness is a marker of adverse outcomes related to comorbidities.

KDIGO defines initial hyporesponsiveness as having no increase in hemoglobin concentration after the first month of appropriate weight-based dosing, and acquired hyporesponsiveness as requiring two increases in ESA doses up to 50% beyond the dose at which the patient had originally been stable.60 Identifying ESA hyporesponsiveness should lead to an intensive search for potentially correctable factors.

The two major factors accounting for the state of hyporesponsiveness are inflammation and iron deficiency.75,76

Inflammation. High C-reactive protein levels have been shown to predict resistance to erythropoietin in dialysis patients.77 The release of cytokines such as tumor necrosis factor alpha, interleukin 1, and interferon gamma has an inhibitory effect on erythropoiesis.78 Additionally, inflammation can alter the response to ESAs by disrupting the metabolism of iron79 through the release of hepcidin, as previously discussed.38 These reasons likely account for the observed lower response to ESAs in the setting of acute illness and explain why ESAs are not recommended for correcting acute anemia.80

Iron deficiency also can blunt the response to ESAs. Large amounts of iron are needed for effective erythropoietic bursts. As such, iron supplementation is now a recognized treatment of renal anemia.81

Other factors associated with hyporesponsiveness include chronic occult blood loss, aluminum toxicity, cobalamin or folate deficiencies, testosterone deficiency, inadequate dialysis, hyperparathyroidism, and superimposed primary bone marrow disease,82,83 and these should be addressed in patients whose anemia does not respond as expected to ESA therapy. A summary of the main causes of ESA hyporesponsiveness, their reversibility, and recommended treatments is presented in Table 3.

Antibody-mediated pure red-cell aplasia. Rarely, patients receiving ESA therapy develop antibodies that neutralize both the ESA and endogenous erythropoietin. The resulting syndrome, called antibody-mediated pure red-cell aplasia, is characterized by the sudden development of severe transfusion-dependent anemia. This has historically been connected to epoetin beta, a formulation not in use in the United States. However, cases have been documented with epoetin alfa and darbepoetin. The incidence rate is low with subcutaneous ESA use, estimated at 0.5 cases per 10,000 patient-years84 and anecdotal with intravenous ESA.85 The definitive diagnosis requires demonstration of neutralizing antibodies against erythropoietin. Parvovirus infection should be excluded as an alternative cause of pure red­cell aplasia.

ANEMIA IN CANCER PATIENTS

ESAs are effective in raising hemoglobin levels and reducing transfusion requirements in patients with chemotherapy-induced anemia.86 However, there are data linking the use of ESAs to shortened survival in patients who have a variety of solid tumors.87

Several mechanisms have been proposed to explain this rapid disease progression, most notably acceleration in tumor growth88–90 by stimulation of erythropoietin receptors on the surface of the tumor cells, leading to increased tumor angiogenesis.91,92

For these reasons, treatment of renal anemia in the setting of active malignancy should be referred to an oncologist.

NOVEL TREATMENTS

Several new agents for treating renal anemia are currently under review.

Continuous erythropoiesis receptor activator

Continuous erythropoiesis receptor activator is a pegylated form of recombinant human erythropoietin that has the ability to repeatedly activate the erythropoietin receptor. It appears to be similar to the other forms of erythropoietin in terms of safety and efficacy in both end-stage renal disease93 and chronic kidney disease.94 It has the advantage of an extended serum half-life, which allows for longer dosing intervals, ie, every 2 weeks. Its use is currently gaining popularity in the dialysis community.

HIF stabilizers

Our growing understanding of the physiology of erythropoietin offers new potential treatment targets. As previously described, production of erythropoietin is stimulated by HIFs. In order to be degraded, these HIFs are hydroxylated at their proline residues by a prolyl hydroxylase. A new category of drugs called prolyl-hydroxylase inhibitors (PDIs) offers the advantage of stabilizing the HIFs, leading to an increase in erythropoietin production.

In phase 1 and 2 clinical trials, these agents have been shown to increase hemoglobin in both end-stage renal disease and chronic kidney disease patients15,16 but not in anephric patients, demonstrating a renal source of the erythropoietin production even in nonfunctioning kidneys. The study of one PDI agent (FG 2216) was halted temporarily after a report of death from fulminant hepatitis, but the other (FG 4592) continues to be studied in a phase 2 clinical trial.95,96

TAKE-HOME POINTS

  • Anemia of renal disease is a common condition that is mainly caused by a decrease in erythropoietin production by the kidneys.
  • While anemia of renal disease can be corrected with ESAs, it is necessary to investigate and rule out underlying treatable conditions such as iron or vitamin deficiencies before giving an ESA.
  • Anemia of renal disease is associated with significant morbidity such as increased risk of left ventricular hypertrophy, myocardial infarction, and heart failure, and has been described as an all-cause mortality multiplier.
  • Unfortunately, the only undisputed benefit of treatment to date remains the avoidance of blood transfusions. Furthermore, the large randomized controlled trials that looked at the benefits of ESA have shown that their use can be associated with increased risk of cardiovascular events. Therefore, use of an ESA in end-stage renal disease should never target a normal hemoglobin levels but rather aim for a hemoglobin level of no more than 11.5 g/dL.
  • Use of an ESA in chronic kidney disease should be individualized and is not recommended to be started unless the hemoglobin level is less than 10 g/dL.
  • Several newer agents for renal anemia are currently under review. A pegylated form of recombinant human erythropoietin has an extended half-life, and a new and promising category of drugs called HIF stabilizers is currently under study.
References
  1. World Health Organization (WHO). Nutritional anaemias: report of a WHO scientific group. Geneva, Switzerland: World Health Organization, 1968.
  2. Hsu CY, McCulloch CE, Curhan GC, et al. Epidemiology of anemia associated with chronic renal insufficiency among adults in the United States: results from the Third National Health and Nutrition Examination Survey. J Am Soc Nephrol 2002; 13:504–510.
  3. Radtke HW, Claussner A, Erbes PM, Scheuermann EH, Schoeppe W, Koch KM. Serum erythropoetin concentration in chronic renal failure: relationship to degree of anemia and excretory renal function. Blood 1979; 54:877–884.
  4. Kazmi WH, Kausz AT, Khan S, et al. Anemia: an early complication of chronic renal insufficiency. Am J Kidney Dis 2001; 38:803–812.
  5. United States Renal Data System. Chapter 3. Morbidity & mortality in patients with CKD. www.usrds.org/2012/view/v1_03.aspx. Accessed June 9, 2016.
  6. Horwich TB, Fonarow GC, Hamilton MA, MacLellan WR, Borenstein J. Anemia is associated with worse symptoms, greater impairment in functional capacity and a significant increase in mortality in patients with advanced heart failure. J Am Coll Cardiol 2002; 39:1780–1786.
  7. Mark DB, Felker GM. B-type natriuretic peptide: a biomarker for all seasons? N Engl J Med 2004; 350:718–720.
  8. Walker AM, Schneider G, Yeaw J, Nordstrom B, Robbins S, Pettitt D. Anemia as a predictor of cardiovascular events in patients with elevated serum creatinine. J Am Soc Nephrol 2006; 17:2293–2298.
  9. Abramson JL, Jurkovitz CT, Vaccarino V, Weintraub WS, McClellan W. Chronic kidney disease, anemia, and incident stroke in a middle-aged, community-based population: the ARIC Study. Kidney Int 2003; 64:610–615.
  10. Sarnak MJ, Tighiouart H, Manjunath G, et al. Anemia as a risk factor for cardiovascular disease in the Atherosclerosis Risk in Communities (ARIC) study. J Am Coll Cardiol 2002; 40:27–33.
  11. McClellan WM, Flanders WD, Langston RD, Jurkovitz C, Presley R. Anemia and renal insufficiency are independent risk factors for death among patients with congestive heart failure admitted to community hospitals: a population-based study. J Am Soc Nephrol 2002; 13:1928–1936.
  12. Xia H, Ebben J, Ma JZ, Collins AJ. Hematocrit levels and hospitalization risks in hemodialysis patients. J Am Soc Nephrol 1999; 10:1309–1316.
  13. Collins AJ, Li S, St Peter W, et al. Death, hospitalization, and economic associations among incident hemodialysis patients with hematocrit values of 36 to 39%. J Am Soc Nephrol 2001; 12:2465–2473.
  14. Agarwal AK. Practical approach to the diagnosis and treatment of anemia associated with CKD in elderly. J Am Med Dir Assoc 2006; 7(suppl 9):S7–S12.
  15. Bernhardt WM, Wiesener MS, Scigalla P, et al. Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD. J Am Soc Nephrol 2010; 21:2151–2156.
  16. Provenzano R, Fadda G, Bernardo M, et al. FG-2216, a novel oral HIF-PHI, stimulates erythropoiesis and increases hemoglobin concentration in patients with non-dialysis CKD. Am J Kidney Dis 2008; 51:B80.
  17. Maxwell PH, Osmond MK, Pugh CW, et al. Identification of the renal erythropoietin-producing cells using transgenic mice. Kidney Int 1993; 44:1149–1162.
  18. Maxwell PH, Ferguson DJ, Nicholls LG, et al. Sites of erythropoietin production. Kidney Int 1997; 51:393–401.
  19. Jelkmann W. Erythropoeitin: structure, control of production and function. Physiol Rev 1992; 72:449–489.
  20. Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 1995; 92:5510–5514.
  21. Wang GL, Semenza GL. Purification and characterization of hypoxia-inducible factor 1. J Biol Chem 1995; 270:1230–1237.
  22. Maxwell PH, Wiesener MS, Chang GW, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 1999; 399:271–275.
  23. Salceda S, Caro J. Hypoxia-inducible factor 1alpha protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. J Biol Chem 1997; 272:22642–22647.
  24. Malik J, Kim AR, Tyre KA, Cherukuri AR, Palis J. Erythropoietin critically regulates the terminal maturation of murine and human primitive erythroblasts. Haematologica 2013; 98:1778–1787.
  25. Wu H, Liu X, Jaenisch R, Lodish HF. Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor. Cell 1995; 83:59–67.
  26. Socolovsky M, Nam H, Fleming MD, Haase VH, Brugnara C, Lodish HF. Ineffective erythropoiesis in Stat5a(-/-)5b(-/-) mice due to decreased survival of early erythroblasts. Blood 2001; 98:3261–3273.
  27. Papanikolaou G, Pantopoulos K. Iron metabolism and toxicity. Toxicol Appl Pharmacol 2005; 202:199–211.
  28. Conrad ME, Umbreit JN. Pathways of iron absorption. Blood Cells Mol Dis 2002; 29:336–355.
  29. Frazer DM, Anderson GJ. The orchestration of body iron intake: how and where do enterocytes receive their cues? Blood Cells Moll Dis 2003; 30:288–297.
  30. Donovan A, Lima CA, Pinkus JL, et al. The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab 2005; 1:191–200.
  31. Vulpe CD, Kuo YM, Murphy TL, et al. Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Nat Genet 1999; 21:195–199.
  32. Bothwell TH. Overview and mechanisms of iron regulation. Nutr Rev 1995: 53:237–245.
  33. Kawabata H, Nakamaki T, Ikonomi P, Smith RD, Germain RS, Koeffler HP. Expression of transferrin receptor 2 in normal and neoplastic hematopoietic cells. Blood 2001; 98:2714–2719.
  34. Arosio P, Levi S. Cytosolic and mitochondrial ferritins in the regulation of cellular iron homeostasis and oxidative damage. Biochim Biophys Acta 2010; 1800:783–792.
  35. Finch CA, Bellotti V, Stray S, et al. Plasma ferritin determination as a diagnostic tool. West J Med 1986; 145:657–663.
  36. Delaby C, Pilard N, Goncalves AS, Beaumont C, Canonne-Hergaux F. Presence of the iron exporter ferroportin at the plasma membrane of macrophages is enhanced by iron loading and down-regulated by hepcidin. Blood 2005; 106:3979–3984.
  37. Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood 2003; 102:783–788.
  38. Nicolas G, Chauvet C, Viatte L, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest 2002; 110:1037–1044.
  39. DeGowin RL, Lavender AR, Forland M, Charleston D, Gottschalk A. Erythropoiesis and erythropoietin in patients with chronic renal failure treated with hemodialysis and testosterone. Ann Intern Med 1970; 72:913–918.
  40. Richardson JR Jr, Weinstein MB. Erythropoietic response of dialyzed patients to testosterone administration. Ann Intern Med 1970; 73:403–407
  41. Eschbach JW, Abdulhadi MH, Browne JK, et al. Recombinant human erythropoietin in anemic patients with end-stage renal disease. Results of a phase III multicenter clinical trial. Ann Intern Med 1989; 111:992–1000.
  42. Moreno F, Aracil FJ, Pérez R, Valderrábano F. Controlled study on the improvement of quality of life in elderly hemodialysis patients after correcting end-stage renal disease-related anemia with erythropoietin. Am J Kidney Dis 1996; 27:548–556.
  43. Nissenson AR, Nimer SD, Wolcott DL. Recombinant human erythropoietin and renal anemia: molecular biology, clinical efficacy, and nervous system effects. Ann Intern Med 1991; 114:402–416.
  44. Stivelman JC. Benefits of anaemia treatment on cognitive function. Nephrol Dial Transplant 2000; 15(suppl 3):29–35.
  45. Maddux FW, Shetty S, del Aguila MA, Nelson MA, Murray BM. Effect of erythropoiesis-stimulating agents on healthcare utilization, costs, and outcomes in chronic kidney disease. Ann Pharmacother 2007; 41:1761–1769.
  46. Macdougall IC, Lewis NP, Saunders MJ, et al. Long-term cardiorespiratory effects of amelioration of renal anaemia by erythropoietin. Lancet 1990; 335:489–493.
  47. Silverberg DS, Wexler D, Blum M, et al. Effects of treatment with epoetin beta on outcomes in patients with anaemia and chronic heart failure. Kidney Blood Press Res 2005; 28:41–47.
  48. Perkins R, Olson S, Hansen J, Lee J, Stiles K, Lebrun C. Impact of an anemia clinic on emergency room visits and hospitalizations in patients with anemia of CKD pre-dialysis. Nephrol Nurs J 2007; 34:167–173, 182.
  49. Locatelli F, Conte F, Marcelli D. The impact of haematocrit levels and erythropoietin treatment on overall and cardiovascular mortality and morbidity—the experience of the Lombardy Dialysis Registry. Nephrol Dial Transplant 1998; 13:1642–1644.
  50. Centers for Medicare and Medicaid Services; Kinney R. 2005 Annual Report: ESRD Clinical Performance Measures Project. Am J Kidney Dis 2006; 48(suppl 2):S1–S106.
  51. US Renal Data System. Annual Data Report 2006. www.usrds.org/adr.aspx. Accessed July 3, 2016.
  52. Besarab A, Bolton WK, Browne JK, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 1998; 339:584–590.
  53. Singh AK, Szczech L, Tang KL, et al; CHOIR Investigators. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006; 355:2085–2098.
  54. Drüeke TB, Locatelli F, Clyne N, et al; CREATE Investigators. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006; 355:2071–2084.
  55. Pfeffer MA, Burdmann EA, Chen CY, et al; TREAT Investigators. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 2009; 361:2019–2032.
  56. Kirkpantur A, Kahraman S, Yilmaz R, et al. The effects of maintenance recombinant human erythropoietin therapy on ambulatory blood pressure recordings: conventional, Doppler, and tissue Doppler echocardiographic parameters. Artif Organs 2005; 29:965–972.
  57. Fishbane S, Berns JS. Hemoglobin cycling in hemodialysis patients treated with recombinant human erythropoietin. Kidney Int 2005; 68:1337–1343.
  58. Szczech LA, Barnhart HX, Inrig JK, et al. Secondary analysis of the CHOIR trial epoetin-alpha dose and achieved hemoglobin outcomes. Kidney Int 2008; 74:791–798.
  59. Solomon SD, Uno H, Lewis EF, et al; Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) Investigators. Erythropoietic response and outcomes in kidney disease and type 2 diabetes. N Engl J Med 2010; 363:1146–1155.
  60. Kidney Disease: Improving Global Outcomes (KDIGO). KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney Int Suppl 2012; 2:279–335.
  61. Fernández-Rodríguez AM, Guindeo-Casasús MC, Molero-Labarta T, et al. Diagnosis of iron deficiency in chronic renal failure. Am J Kidney Dis 1999; 34:508–513.
  62. Eschbach JW, Cook JD, Scribner BH, Finch CA. Iron balance in hemodialysis patients. Ann Intern Med 1977; 87:710–713.
  63. Mittman N, Sreedhara R, Mushnick R, et al. Reticulocyte hemoglobin content predicts functional iron deficiency in hemodialysis patients receiving rHuEPO. Am J Kidney Dis 1997; 30:912–922.
  64. Tessitore N, Solero GP, Lippi G, et al. The role of iron status markers in predicting response to intravenous iron in haemodialysis patients on maintenance erythropoietin. Nephrol Dial Transplant 2001; 16:1416–1423.
  65. Coyne DW. Iron indices: what do they really mean? Kidney Int Suppl 2006; 101:S4–S8.
  66. Fishbane S, Kowalski EA, Imbriano LJ, Maesaka JK. The evaluation of iron status in hemodialysis patients. J Am Soc Nephrol 1996; 7:2654–2657.
  67. Coyne DW, Kapoian T, Suki W, et al; DRIVE Study Group. Ferric gluconate is highly efficacious in anemic hemodialysis patients with high serum ferritin and low transferrin saturation: results of the Dialysis Patients’ Response to IV Iron with Elevated Ferritin (DRIVE) Study. J Am Soc Nephrol 2007; 18:975–984.
  68. Radtke HW, Claussner A, Erbes PM, Scheuermann EH, Schoeppe W, Koch KM. Serum erythropoietin concentration in chronic renal failure: relationship to degree of anemia and excretory renal function. Blood 1979; 54:877–884.
  69. Korte W, Cogliatti SB, Jung K, Riesen W. Mild renal dysfunction is sufficient to induce erythropoietin deficiency in patients with unexplained anaemia. Clin Chim Acta 2000; 292:149–154.
  70. Locatelli F, Olivares J, Walker R, et al; European/Australian NESP 980202 Study Group. Novel erythropoiesis stimulating protein for treatment of anemia in chronic renal insufficiency. Kidney Int 2001; 60:741–747.
  71. Carrera F, Burnier M. Use of darbepoetin alfa in the treatment of anaemia of chronic kidney disease: clinical and pharmacoeconomic considerations. NDT Plus 2009; 2(suppl 1):i9–i17.
  72. Egrie JC, Browne JK. Development and characterization of novel erythropoiesis stimulating protein (NESP). Nephrol Dial Transplant 2001; 16(suppl 3):3–13.
  73. Nissenson AR, Charytan C. Controversies in iron management. Kidney Int Suppl 2003; 87:S64–S71.
  74. Kilpatrick RD, Critchlow CW, Fishbane S, et al. Greater epoetin alpha responsiveness is associated with improved survival in hemodialysis patients. Clin J Am Soc Nephrol 2008; 3:1077–1083.
  75. Locatelli F, Aljama P, Barany P, et al; European Best Practice Guidelines Working Group. Revised European best practice guidelines for the management of anaemia in patients with chronic renal failure. Nephrol Dial Transplant 2004; 19(suppl 2):ii1–ii47.
  76. Stenvinkel P. The role of inflammation in the anaemia of end-stage renal disease. Nephrol Dial Transplant 2001; 16(suppl 7):36–40.
  77. Barany P, Divino Filho JC, Bergstrom J. High C-reactive protein is a strong predictor of resistance to erythropoietin in hemodialysis patients. Am J Kidney Dis 1997; 29:565–568.
  78. Drueke T. Hyporesponsiveness to recombinant human erythropoietin. Nephrol Dial Transplant 2001; 16(suppl 7):25–28.
  79. Casadevall N. Cellular mechanism of resistance to erythropoietin. Nephrol Dial Transplant 1995; 10(suppl 6):27–30.
  80. Kraus E, Rabb H. EPO therapy during acute kidney disease: to use or not to use, that is the question. Am J Kidney Dis 2005; 46:967–969.
  81. Gotloib L, Silverberg D, Fudin R, Shostak A. Iron deficiency is a common cause of anemia in chronic kidney disease and can often be corrected with intravenous iron. J Nephrol 2006; 19:161–167.
  82. Tarng DC, Huang TP, Chen TW, Yang WC. Erythropoietin hyporesponsiveness: from iron deficiency to iron overload. Kidney Int Suppl 1999; 69:S107–S118.
  83. Drüeke TB. Modulating factors in the hematopoietic response to erythropoietin. Am J Kidney Dis 1991; 18(suppl 1):87–92.
  84. Boven K, Stryker S, Knight J, et al. The increased incidence of pure red cell aplasia with an Eprex formulation in uncoated rubber stopper syringes. Kidney Int 2005; 67:2346–2353.
  85. Shimizu H, Saitoh T, Ota F, et al. Pure red cell aplasia induced only by intravenous administration of recombinant human erythropoietin. Acta Haematol 2011; 126:114–118.
  86. Tonia T, Mettler A, Robert N, et al. Erythropoietin or darbepoetin for patients with cancer. Cochrane Database Syst Rev 2012; 12:CD003407.
  87. Bohlius J, Langensiepen S, Schwarzer G, et al. Recombinant human erythropoietin and overall survival in cancer patients: results of a comprehensive meta-analysis. J Natl Cancer Inst 2005; 97:489–498.
  88. Henke M, Laszig R, Rübe C, et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet 2003; 362:1255–1260.
  89. Leyland-Jones B, Semiglazov V, Pawlicki M, et al. Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study. J Clin Oncol 2005; 23:5960–5972.
  90. Brower V. Erythropoietin may impair, not improve, cancer survival. Nat Med 2003; 9:1439.
  91. Acs G, Acs P, Beckwith SM, et al. Erythropoietin and erythropoietin receptor expression in human cancer. Cancer Res 2001; 61:3561–3565.
  92. Yasuda Y, Fujita Y, Matsuo T, et al. Erythropoietin regulates tumour growth of human malignancies. Carcinogenesis 2003; 24:1021–1029.
  93. Levin NW, Fishbane S, Cañedo FV, et al; MAXIMA Study Investigators. Intravenous methoxy polyethylene glycol-epoetin beta for haemoglobin control in patients with chronic kidney disease who are on dialysis: a randomised non-inferiority trial (MAXIMA). Lancet 2007; 370:1415–1421.
  94. Macdougall IC, Walker R, Provenzano R, et al; ARCTOS Study Investigators. C.E.R.A. corrects anemia in patients with chronic kidney disease not on dialysis: results of a randomized clinical trial. Clin J Am Soc Nephrol 2008; 3:337–347.
  95. Frohna PA, Milwee S, Pinkett J, et al. Preliminary results from a randomized, single-blind, placebo-controlled trial of FG-4592, a novel hypoxia inducible factor prolyl hydroxylase inhibitor, in subjects with CKD anemia (abstract). J Am Soc Nephrol 2007; 18:763.
  96. Holdstock L, Meadowcroft AM, Maier R, et al. Four-week studies of oral hypoxia-inducible factor-prolyl hydroxylase inhibitor GSK1278863 for treatment of anemia. J Am Soc Nephrol 2016; 27:1234–1244.
References
  1. World Health Organization (WHO). Nutritional anaemias: report of a WHO scientific group. Geneva, Switzerland: World Health Organization, 1968.
  2. Hsu CY, McCulloch CE, Curhan GC, et al. Epidemiology of anemia associated with chronic renal insufficiency among adults in the United States: results from the Third National Health and Nutrition Examination Survey. J Am Soc Nephrol 2002; 13:504–510.
  3. Radtke HW, Claussner A, Erbes PM, Scheuermann EH, Schoeppe W, Koch KM. Serum erythropoetin concentration in chronic renal failure: relationship to degree of anemia and excretory renal function. Blood 1979; 54:877–884.
  4. Kazmi WH, Kausz AT, Khan S, et al. Anemia: an early complication of chronic renal insufficiency. Am J Kidney Dis 2001; 38:803–812.
  5. United States Renal Data System. Chapter 3. Morbidity & mortality in patients with CKD. www.usrds.org/2012/view/v1_03.aspx. Accessed June 9, 2016.
  6. Horwich TB, Fonarow GC, Hamilton MA, MacLellan WR, Borenstein J. Anemia is associated with worse symptoms, greater impairment in functional capacity and a significant increase in mortality in patients with advanced heart failure. J Am Coll Cardiol 2002; 39:1780–1786.
  7. Mark DB, Felker GM. B-type natriuretic peptide: a biomarker for all seasons? N Engl J Med 2004; 350:718–720.
  8. Walker AM, Schneider G, Yeaw J, Nordstrom B, Robbins S, Pettitt D. Anemia as a predictor of cardiovascular events in patients with elevated serum creatinine. J Am Soc Nephrol 2006; 17:2293–2298.
  9. Abramson JL, Jurkovitz CT, Vaccarino V, Weintraub WS, McClellan W. Chronic kidney disease, anemia, and incident stroke in a middle-aged, community-based population: the ARIC Study. Kidney Int 2003; 64:610–615.
  10. Sarnak MJ, Tighiouart H, Manjunath G, et al. Anemia as a risk factor for cardiovascular disease in the Atherosclerosis Risk in Communities (ARIC) study. J Am Coll Cardiol 2002; 40:27–33.
  11. McClellan WM, Flanders WD, Langston RD, Jurkovitz C, Presley R. Anemia and renal insufficiency are independent risk factors for death among patients with congestive heart failure admitted to community hospitals: a population-based study. J Am Soc Nephrol 2002; 13:1928–1936.
  12. Xia H, Ebben J, Ma JZ, Collins AJ. Hematocrit levels and hospitalization risks in hemodialysis patients. J Am Soc Nephrol 1999; 10:1309–1316.
  13. Collins AJ, Li S, St Peter W, et al. Death, hospitalization, and economic associations among incident hemodialysis patients with hematocrit values of 36 to 39%. J Am Soc Nephrol 2001; 12:2465–2473.
  14. Agarwal AK. Practical approach to the diagnosis and treatment of anemia associated with CKD in elderly. J Am Med Dir Assoc 2006; 7(suppl 9):S7–S12.
  15. Bernhardt WM, Wiesener MS, Scigalla P, et al. Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD. J Am Soc Nephrol 2010; 21:2151–2156.
  16. Provenzano R, Fadda G, Bernardo M, et al. FG-2216, a novel oral HIF-PHI, stimulates erythropoiesis and increases hemoglobin concentration in patients with non-dialysis CKD. Am J Kidney Dis 2008; 51:B80.
  17. Maxwell PH, Osmond MK, Pugh CW, et al. Identification of the renal erythropoietin-producing cells using transgenic mice. Kidney Int 1993; 44:1149–1162.
  18. Maxwell PH, Ferguson DJ, Nicholls LG, et al. Sites of erythropoietin production. Kidney Int 1997; 51:393–401.
  19. Jelkmann W. Erythropoeitin: structure, control of production and function. Physiol Rev 1992; 72:449–489.
  20. Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 1995; 92:5510–5514.
  21. Wang GL, Semenza GL. Purification and characterization of hypoxia-inducible factor 1. J Biol Chem 1995; 270:1230–1237.
  22. Maxwell PH, Wiesener MS, Chang GW, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 1999; 399:271–275.
  23. Salceda S, Caro J. Hypoxia-inducible factor 1alpha protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. J Biol Chem 1997; 272:22642–22647.
  24. Malik J, Kim AR, Tyre KA, Cherukuri AR, Palis J. Erythropoietin critically regulates the terminal maturation of murine and human primitive erythroblasts. Haematologica 2013; 98:1778–1787.
  25. Wu H, Liu X, Jaenisch R, Lodish HF. Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor. Cell 1995; 83:59–67.
  26. Socolovsky M, Nam H, Fleming MD, Haase VH, Brugnara C, Lodish HF. Ineffective erythropoiesis in Stat5a(-/-)5b(-/-) mice due to decreased survival of early erythroblasts. Blood 2001; 98:3261–3273.
  27. Papanikolaou G, Pantopoulos K. Iron metabolism and toxicity. Toxicol Appl Pharmacol 2005; 202:199–211.
  28. Conrad ME, Umbreit JN. Pathways of iron absorption. Blood Cells Mol Dis 2002; 29:336–355.
  29. Frazer DM, Anderson GJ. The orchestration of body iron intake: how and where do enterocytes receive their cues? Blood Cells Moll Dis 2003; 30:288–297.
  30. Donovan A, Lima CA, Pinkus JL, et al. The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab 2005; 1:191–200.
  31. Vulpe CD, Kuo YM, Murphy TL, et al. Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Nat Genet 1999; 21:195–199.
  32. Bothwell TH. Overview and mechanisms of iron regulation. Nutr Rev 1995: 53:237–245.
  33. Kawabata H, Nakamaki T, Ikonomi P, Smith RD, Germain RS, Koeffler HP. Expression of transferrin receptor 2 in normal and neoplastic hematopoietic cells. Blood 2001; 98:2714–2719.
  34. Arosio P, Levi S. Cytosolic and mitochondrial ferritins in the regulation of cellular iron homeostasis and oxidative damage. Biochim Biophys Acta 2010; 1800:783–792.
  35. Finch CA, Bellotti V, Stray S, et al. Plasma ferritin determination as a diagnostic tool. West J Med 1986; 145:657–663.
  36. Delaby C, Pilard N, Goncalves AS, Beaumont C, Canonne-Hergaux F. Presence of the iron exporter ferroportin at the plasma membrane of macrophages is enhanced by iron loading and down-regulated by hepcidin. Blood 2005; 106:3979–3984.
  37. Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood 2003; 102:783–788.
  38. Nicolas G, Chauvet C, Viatte L, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest 2002; 110:1037–1044.
  39. DeGowin RL, Lavender AR, Forland M, Charleston D, Gottschalk A. Erythropoiesis and erythropoietin in patients with chronic renal failure treated with hemodialysis and testosterone. Ann Intern Med 1970; 72:913–918.
  40. Richardson JR Jr, Weinstein MB. Erythropoietic response of dialyzed patients to testosterone administration. Ann Intern Med 1970; 73:403–407
  41. Eschbach JW, Abdulhadi MH, Browne JK, et al. Recombinant human erythropoietin in anemic patients with end-stage renal disease. Results of a phase III multicenter clinical trial. Ann Intern Med 1989; 111:992–1000.
  42. Moreno F, Aracil FJ, Pérez R, Valderrábano F. Controlled study on the improvement of quality of life in elderly hemodialysis patients after correcting end-stage renal disease-related anemia with erythropoietin. Am J Kidney Dis 1996; 27:548–556.
  43. Nissenson AR, Nimer SD, Wolcott DL. Recombinant human erythropoietin and renal anemia: molecular biology, clinical efficacy, and nervous system effects. Ann Intern Med 1991; 114:402–416.
  44. Stivelman JC. Benefits of anaemia treatment on cognitive function. Nephrol Dial Transplant 2000; 15(suppl 3):29–35.
  45. Maddux FW, Shetty S, del Aguila MA, Nelson MA, Murray BM. Effect of erythropoiesis-stimulating agents on healthcare utilization, costs, and outcomes in chronic kidney disease. Ann Pharmacother 2007; 41:1761–1769.
  46. Macdougall IC, Lewis NP, Saunders MJ, et al. Long-term cardiorespiratory effects of amelioration of renal anaemia by erythropoietin. Lancet 1990; 335:489–493.
  47. Silverberg DS, Wexler D, Blum M, et al. Effects of treatment with epoetin beta on outcomes in patients with anaemia and chronic heart failure. Kidney Blood Press Res 2005; 28:41–47.
  48. Perkins R, Olson S, Hansen J, Lee J, Stiles K, Lebrun C. Impact of an anemia clinic on emergency room visits and hospitalizations in patients with anemia of CKD pre-dialysis. Nephrol Nurs J 2007; 34:167–173, 182.
  49. Locatelli F, Conte F, Marcelli D. The impact of haematocrit levels and erythropoietin treatment on overall and cardiovascular mortality and morbidity—the experience of the Lombardy Dialysis Registry. Nephrol Dial Transplant 1998; 13:1642–1644.
  50. Centers for Medicare and Medicaid Services; Kinney R. 2005 Annual Report: ESRD Clinical Performance Measures Project. Am J Kidney Dis 2006; 48(suppl 2):S1–S106.
  51. US Renal Data System. Annual Data Report 2006. www.usrds.org/adr.aspx. Accessed July 3, 2016.
  52. Besarab A, Bolton WK, Browne JK, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 1998; 339:584–590.
  53. Singh AK, Szczech L, Tang KL, et al; CHOIR Investigators. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006; 355:2085–2098.
  54. Drüeke TB, Locatelli F, Clyne N, et al; CREATE Investigators. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006; 355:2071–2084.
  55. Pfeffer MA, Burdmann EA, Chen CY, et al; TREAT Investigators. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 2009; 361:2019–2032.
  56. Kirkpantur A, Kahraman S, Yilmaz R, et al. The effects of maintenance recombinant human erythropoietin therapy on ambulatory blood pressure recordings: conventional, Doppler, and tissue Doppler echocardiographic parameters. Artif Organs 2005; 29:965–972.
  57. Fishbane S, Berns JS. Hemoglobin cycling in hemodialysis patients treated with recombinant human erythropoietin. Kidney Int 2005; 68:1337–1343.
  58. Szczech LA, Barnhart HX, Inrig JK, et al. Secondary analysis of the CHOIR trial epoetin-alpha dose and achieved hemoglobin outcomes. Kidney Int 2008; 74:791–798.
  59. Solomon SD, Uno H, Lewis EF, et al; Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) Investigators. Erythropoietic response and outcomes in kidney disease and type 2 diabetes. N Engl J Med 2010; 363:1146–1155.
  60. Kidney Disease: Improving Global Outcomes (KDIGO). KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney Int Suppl 2012; 2:279–335.
  61. Fernández-Rodríguez AM, Guindeo-Casasús MC, Molero-Labarta T, et al. Diagnosis of iron deficiency in chronic renal failure. Am J Kidney Dis 1999; 34:508–513.
  62. Eschbach JW, Cook JD, Scribner BH, Finch CA. Iron balance in hemodialysis patients. Ann Intern Med 1977; 87:710–713.
  63. Mittman N, Sreedhara R, Mushnick R, et al. Reticulocyte hemoglobin content predicts functional iron deficiency in hemodialysis patients receiving rHuEPO. Am J Kidney Dis 1997; 30:912–922.
  64. Tessitore N, Solero GP, Lippi G, et al. The role of iron status markers in predicting response to intravenous iron in haemodialysis patients on maintenance erythropoietin. Nephrol Dial Transplant 2001; 16:1416–1423.
  65. Coyne DW. Iron indices: what do they really mean? Kidney Int Suppl 2006; 101:S4–S8.
  66. Fishbane S, Kowalski EA, Imbriano LJ, Maesaka JK. The evaluation of iron status in hemodialysis patients. J Am Soc Nephrol 1996; 7:2654–2657.
  67. Coyne DW, Kapoian T, Suki W, et al; DRIVE Study Group. Ferric gluconate is highly efficacious in anemic hemodialysis patients with high serum ferritin and low transferrin saturation: results of the Dialysis Patients’ Response to IV Iron with Elevated Ferritin (DRIVE) Study. J Am Soc Nephrol 2007; 18:975–984.
  68. Radtke HW, Claussner A, Erbes PM, Scheuermann EH, Schoeppe W, Koch KM. Serum erythropoietin concentration in chronic renal failure: relationship to degree of anemia and excretory renal function. Blood 1979; 54:877–884.
  69. Korte W, Cogliatti SB, Jung K, Riesen W. Mild renal dysfunction is sufficient to induce erythropoietin deficiency in patients with unexplained anaemia. Clin Chim Acta 2000; 292:149–154.
  70. Locatelli F, Olivares J, Walker R, et al; European/Australian NESP 980202 Study Group. Novel erythropoiesis stimulating protein for treatment of anemia in chronic renal insufficiency. Kidney Int 2001; 60:741–747.
  71. Carrera F, Burnier M. Use of darbepoetin alfa in the treatment of anaemia of chronic kidney disease: clinical and pharmacoeconomic considerations. NDT Plus 2009; 2(suppl 1):i9–i17.
  72. Egrie JC, Browne JK. Development and characterization of novel erythropoiesis stimulating protein (NESP). Nephrol Dial Transplant 2001; 16(suppl 3):3–13.
  73. Nissenson AR, Charytan C. Controversies in iron management. Kidney Int Suppl 2003; 87:S64–S71.
  74. Kilpatrick RD, Critchlow CW, Fishbane S, et al. Greater epoetin alpha responsiveness is associated with improved survival in hemodialysis patients. Clin J Am Soc Nephrol 2008; 3:1077–1083.
  75. Locatelli F, Aljama P, Barany P, et al; European Best Practice Guidelines Working Group. Revised European best practice guidelines for the management of anaemia in patients with chronic renal failure. Nephrol Dial Transplant 2004; 19(suppl 2):ii1–ii47.
  76. Stenvinkel P. The role of inflammation in the anaemia of end-stage renal disease. Nephrol Dial Transplant 2001; 16(suppl 7):36–40.
  77. Barany P, Divino Filho JC, Bergstrom J. High C-reactive protein is a strong predictor of resistance to erythropoietin in hemodialysis patients. Am J Kidney Dis 1997; 29:565–568.
  78. Drueke T. Hyporesponsiveness to recombinant human erythropoietin. Nephrol Dial Transplant 2001; 16(suppl 7):25–28.
  79. Casadevall N. Cellular mechanism of resistance to erythropoietin. Nephrol Dial Transplant 1995; 10(suppl 6):27–30.
  80. Kraus E, Rabb H. EPO therapy during acute kidney disease: to use or not to use, that is the question. Am J Kidney Dis 2005; 46:967–969.
  81. Gotloib L, Silverberg D, Fudin R, Shostak A. Iron deficiency is a common cause of anemia in chronic kidney disease and can often be corrected with intravenous iron. J Nephrol 2006; 19:161–167.
  82. Tarng DC, Huang TP, Chen TW, Yang WC. Erythropoietin hyporesponsiveness: from iron deficiency to iron overload. Kidney Int Suppl 1999; 69:S107–S118.
  83. Drüeke TB. Modulating factors in the hematopoietic response to erythropoietin. Am J Kidney Dis 1991; 18(suppl 1):87–92.
  84. Boven K, Stryker S, Knight J, et al. The increased incidence of pure red cell aplasia with an Eprex formulation in uncoated rubber stopper syringes. Kidney Int 2005; 67:2346–2353.
  85. Shimizu H, Saitoh T, Ota F, et al. Pure red cell aplasia induced only by intravenous administration of recombinant human erythropoietin. Acta Haematol 2011; 126:114–118.
  86. Tonia T, Mettler A, Robert N, et al. Erythropoietin or darbepoetin for patients with cancer. Cochrane Database Syst Rev 2012; 12:CD003407.
  87. Bohlius J, Langensiepen S, Schwarzer G, et al. Recombinant human erythropoietin and overall survival in cancer patients: results of a comprehensive meta-analysis. J Natl Cancer Inst 2005; 97:489–498.
  88. Henke M, Laszig R, Rübe C, et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet 2003; 362:1255–1260.
  89. Leyland-Jones B, Semiglazov V, Pawlicki M, et al. Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study. J Clin Oncol 2005; 23:5960–5972.
  90. Brower V. Erythropoietin may impair, not improve, cancer survival. Nat Med 2003; 9:1439.
  91. Acs G, Acs P, Beckwith SM, et al. Erythropoietin and erythropoietin receptor expression in human cancer. Cancer Res 2001; 61:3561–3565.
  92. Yasuda Y, Fujita Y, Matsuo T, et al. Erythropoietin regulates tumour growth of human malignancies. Carcinogenesis 2003; 24:1021–1029.
  93. Levin NW, Fishbane S, Cañedo FV, et al; MAXIMA Study Investigators. Intravenous methoxy polyethylene glycol-epoetin beta for haemoglobin control in patients with chronic kidney disease who are on dialysis: a randomised non-inferiority trial (MAXIMA). Lancet 2007; 370:1415–1421.
  94. Macdougall IC, Walker R, Provenzano R, et al; ARCTOS Study Investigators. C.E.R.A. corrects anemia in patients with chronic kidney disease not on dialysis: results of a randomized clinical trial. Clin J Am Soc Nephrol 2008; 3:337–347.
  95. Frohna PA, Milwee S, Pinkett J, et al. Preliminary results from a randomized, single-blind, placebo-controlled trial of FG-4592, a novel hypoxia inducible factor prolyl hydroxylase inhibitor, in subjects with CKD anemia (abstract). J Am Soc Nephrol 2007; 18:763.
  96. Holdstock L, Meadowcroft AM, Maier R, et al. Four-week studies of oral hypoxia-inducible factor-prolyl hydroxylase inhibitor GSK1278863 for treatment of anemia. J Am Soc Nephrol 2016; 27:1234–1244.
Issue
Cleveland Clinic Journal of Medicine - 83(8)
Issue
Cleveland Clinic Journal of Medicine - 83(8)
Page Number
613-624
Page Number
613-624
Publications
Publications
Topics
Article Type
Display Headline
Anemia of chronic kidney disease: Treat it, but not too aggressively
Display Headline
Anemia of chronic kidney disease: Treat it, but not too aggressively
Legacy Keywords
anemia, chronic kidney disease, erythropoietin, erythropoiesis-stimulating agents, ESAs, hypoxia-inducible factor, HIF, iron, Georges Nakhoul, James Simon
Legacy Keywords
anemia, chronic kidney disease, erythropoietin, erythropoiesis-stimulating agents, ESAs, hypoxia-inducible factor, HIF, iron, Georges Nakhoul, James Simon
Sections
Inside the Article

KEY POINTS

  • Before treating with ESAs, it is necessary to investigate and rule out underlying treatable conditions such as iron or vitamin deficiencies.
  • Recognizing anemia in chronic kidney disease is important and often involves participation by the primary care physician, especially in early disease when chronic kidney disease may be mild.
  • The only proven benefit of ESA therapy is avoidance of blood transfusions.
  • ESAs should not be used to increase the hemoglobin concentration above 13 g/dL. In end-stage renal disease, the goal of therapy is to maintain levels at a target no higher than 11.5 g/dL. In nondialysis-dependent chronic kidney disease, the decision to prescribe ESA therapy should be individualized.
Disallow All Ads
Alternative CME
Article PDF Media